Azacyclic compounds

ABSTRACT

Compounds and methods are provided for the treatment of disease conditions in which modification of serotonergic receptor activity has a beneficial effect. In the method, an effective amount of a compound is administered to a patient in need of such treatment.

This application claims the benefit of priority from copending U.S.Provisional Application Ser. No. 60/187,289 filed Mar. 6, 2000

FIELD OF THE INVENTION

The present invention relates to novel compounds that affect monoaminereceptors, including serotonin receptors. The invention specificallyprovides compounds that are active as inverse agonists, and thereforealso as antagonists, at the 5-HT2A subtype of human serotonin receptors.The invention also provides methods, utilizing the compounds of theinvention for modulating 5-HT2A receptor-mediated events, that areuseful for treating or alleviating disease conditions in whichmodification of the activity of these receptors is beneficial.

BACKGROUND OF THE INVENTION

Serotonin or 5-hydroxytryptamine (5-HT) plays a significant role in thefunctioning of the mammalian body. In the central nervous system, 5-HTis an important neurotransmitter and neuromodulator that is implicatedin such diverse behaviors and responses as sleeping, eating, locomotion,perceiving pain, learning and memory, sexual behavior, controlling bodytemperature and blood pressure. In the spinal column, serotonin plays animportant role in the control systems of the afferent peripheralnociceptors (Moulignier, Rev. Neurol. 150:3-15, (1994)). Peripheralfunctions in the cardiovascular, hematological and gastrointestinalsystems have also been ascribed to 5-HT. 5-HT has been found to mediatea variety of contractile, secretory, and electrophysiologic effectsincluding vascular and nonvascular smooth muscle contraction, andplatelet aggregation. (Fuller, Biology of Serotonergic Transmission,1982; Boullin, Serotonin In Mental Abnormalities 1:316 (1978); Barchas,et al., Serotonin and Behavior, (1973)). The 5-HT2A receptor subtype(also referered to as subclass) is widely yet discretely expressed inthe human brain, including many cortical, limbic, and forebrain regionspostulated to be involved in the modulation of higher cognitive andaffective functions. This receptor subtype is also expressed on matureplatelets where it mediates, in part, platelet aggregation, one of theinitial steps in the process of vascular thrombosis.

Given the broad distribution of serotonin within the body, it isunderstandable that tremendous interest in drugs that affectserotonergic systems exists (Gershon, et al., The Peripheral Actions of5-Hydroxytryptamine, 246 (1989); Saxena, et al., J. CardiovascularPharmacol. 15: Supp. 7 (1990)). Serotonin receptors are members of alarge human gene family of membrane-spanning proteins that function astransducers of intercellular communication. They exist on the surface ofvarious cell types, including neurons and platelets, where, upon theiractivation by either their endogenous ligand serotonin or exogenouslyadministered drugs, they change their conformational structure andsubsequently interact with downstream mediators of cellular signaling.Many of these receptors, including the 5-HT2A subclass, are G-proteincoupled receptors (GPCRs) that signal by activating guanine nucleotidebinding proteins (G-proteins), resulting in the generation, orinhibition of, second messenger molecules such as cyclic AMP, inositolphosphates, and diacylglycerol.

These second messengers then modulate the function of a variety ofintracellular enzymes, including kinases and ion channels, whichultimately affect cellular excitability and function.

At least 15 genetically distinct 5-HT receptor subtypes have beenidentified and assigned to one of seven families (5-HT1-7). Each subtypedisplays a unique distribution, preference for various ligands, andfunctional correlate(s).

Serotonin may be an important component in various types of pathologicalconditions such as certain psychiatric disorders (depression,aggressiveness, panic attacks, obsessive compulsive disorders,psychosis, schizophrenia, suicidal tendency), certain neurodegenerativedisorders (Alzheimer-type dementia, Parkinsonism, Huntington's chorea),anorexia, bulimia, disorders associated with alcoholism, cerebralvascular accidents, and migraine (Meltzer, Neuropsychopharmacology,21:106S-115S (1999); Barnes & Sharp, Neuropharmacology, 38:1083-1152(1999); Glennon, Neurosci. Biobehavioral Rev., 14:35 (1990)). Recentevidence strongly implicates the 5-HT2 receptor subtype in the etiologyof such medical conditions as hypertension, thrombosis, migraine,vasospasm, ischemia, depression, anxiety, psychosis, schizophrenia,sleep disorders and appetite disorders.

Schizophrenia is a particularly devastating neuropsychiatric disorderthat affects approximately 1% of the human population. It has beenestimated that the total financial cost for the diagnosis, treatment,and lost societal productivity of individuals affected by this diseaseexceeds 2% of the gross national product (GNP) of the United States.Current treatment primarily involves pharmacotherapy with a class ofdrugs known as antipsychotics. Antipsychotics are effective inameliorating positive symptoms (e.g., hallucinations and delusions), yetthey frequently do not improve negative symptoms (e.g., social andemotional withdrawal, apathy, and poverty of speech).

Currently, nine major classes of antipsychotics are prescribed to treatpsychotic symptoms. Use of these compounds is limited, however, by theirside effect profiles. Nearly all of the “typical” or older generationcompounds have significant adverse effects on human motor function.These “extrapyramidal” side effects, so termed due to their effects onmodulatory human motor systems, can be both acute (e.g., dystonicreactions, a potentially life threatening but rare neuroleptic malignantsyndrome) and chronic (e.g., akathisias, tremors, and tardivedyskinesia). Drug development efforts have, therefore, focused on newer“atypical” agents free of these adverse effects.

Antipsychotic drugs have been shown to interact with a large number ofcentral monoaminergic neurotransmitter receptors, includingdopaminergic, serotonergic, adrenergic, muscarinic, and histaminergicreceptors. It is likely that the therapeutic and adverse effects ofthese drugs are mediated by distinct receptor subtypes. The high degreeof genetic and pharmacological homology between these receptor subtypeshas hampered the development of subtype-selective compounds, as well asthe determination of the normal physiologic or pathophysiologic role ofany particular receptor subtype. Thus there is a need to develop drugsthat are selective for individual receptor classes and subclassesamongst monoaminergic neurotransmitter receptors.

The prevailing theory for the mechanism of action of antipsychotic drugsinvolves antagonism of dopamine D2 receptors. Unfortunately, it islikely that antagonism of dopamine D2 receptors also mediates theextrapyramidal side effects. Antagonism of 5-HT2A is an alternatemolecular mechanism for drugs with antipsychotic efficacy, possiblythrough antagonism of heightened or exaggerated signal transductionthrough serotonergic systems. 5-HT2A antagonists are therefore goodcandidates for treating psychosis without extrapyramidal side effects.

Traditionally, these receptors have been assumed to exist in a quiescentstate unless activated by the binding of an agonist (a drug thatactivates a receptor). It is now appreciated that many, if not most, ofthe GPCR monoamine receptors, including serotonin receptors, can existin a partially activated state in the absence of their endogenousagonists. This increased basal activity (constitutive activity) can beinhibited by compounds called inverse agonists. Both agonists andinverse agonists possess intrinsic activity at a receptor, in that theyalone can activate or inactivate these molecules, respectively. Incontrast, classic or neutral antagonists compete against agonists andinverse agonists for access to the receptor, but do not possess theintrinsic ability to inhibit elevated basal or constitutive receptorresponses.

We have recently elucidated an important aspect of 5-HT2A receptorfunction by applying the Receptor Selection and Amplification Technology(U.S. Pat. No. 5,707,798, 1998; Chem Abstr. 128:111548 (1998) andcitations therein), to the study of the 5-HT2 subclass of serotoninreceptors. R-SAT is a phenotypic assay of receptor function thatinvolves the heterologous expression of receptors in mammalianfibroblasts. Using this technology we were able to demonstrate thatnative 5-HT2A receptors possess significant constitutive, oragonist-independent, receptor activity (U.S. Patent Application Ser. No.60/103,317, herein incorportated by reference). Furthermore, by directlytesting a large number of centrally acting medicinal compounds withknown clinical activity in neuropsychiatric disease, we determined thatcompounds with antipsychotic efficacy all shared a common molecularproperty. Nearly all of these compounds, which are used by psychiatriststo treat psychosis, were found to be potent 5-HT2A inverse agonists.This unique clinico-pharmacologic correlation at a single receptorsubtype is compelling evidence that 5-HT2A receptor inverse agonism is amolecular mechanism of antipsychotic efficacy in humans.

Detailed pharmacological characterization of a large number ofantipsychotic compounds revealed that they possess broad activity atmultiple related receptor subtypes. Most of these compounds displayagonist, competitive antagonist, or inverse agonist activity at multiplemonoaminergic receptor subtypes, including serotoninergic, dopaminergic,adrenergic, muscarinic and histaminergic receptors. This broad activityis likely responsible for the sedating, hypotensive, and motor sideeffects of these compounds. It would therefore be of great advantage todevelop compounds that are selective inverse agonists of the 5-HT2Areceptor, but which have little or no activity on other monaminereceptors subtypes, especially dopamine D2 receptors. Such compounds maybe useful in the treatment of human disease (e.g., as anti-psychotics),and may avoid the adverse side effects associated with non-selectivereceptor interactions.

SUMMARY OF THE INVENTION

The present invention provides compounds of the general formula (I) thataffect monoamine receptors, especially serotonin receptors, and share asa common property inverse agonist activity at the 5-HT2A subtype ofhuman serotonin receptors:

wherein

Z is a group selected from

R is hydrogen, a cyclic or straight-chained or branched acyclic organylgroup, a lower hydroxyalkyl group, a lower aminoalkyl group, or anaralkyl or heteroaralkyl group;

n is 0, 1, or 2;

X₁ is methylene, vinylene,or an NH or N(lower alkyl) group;and

X₂ is methylene, or, when X₁ is methylene or vinylene, X₂ is methyleneor a bond; or when X₁ is methylene, X₂ is O, S, NH, or N(lower alkyl) ora bond;

Y₁ is methylene and Y₂ is methylene, vinylene, ethylene, propylene, or abond; or

Y₁ is a bond and Y₂ is vinylene; or

Y₁ is ethylene and Y₂ is O, S, NH, or N(lower alkyl);

Ar₁ and Ar₂ independently are unsubstituted or substituted aryl orheteroaryl groups;

W is oxygen or sulfur; or

a pharmaceutically acceptable salt, ester, or prodrug thereof.

The present invention also provides pharmaceutical compositionscomprising an effective amount of a compound of formula (I) orpharmaceutically acceptable salts, esters, or prodrugs thereof.

Also provided are methods of inhibiting an activity of a monoaminereceptor comprising contacting the monoamine receptor or a systemcontaining the monoamine receptor with an effective amount of a compoundof formula (I), as well as kits for performing the same. Preferably, thereceptor is a serotonin receptor of the 5-HT2A subclass. The receptormay be located in either the central or peripheral nervous system, bloodcells or platelets, and may be mutated or modified. In a preferredembodiment, the receptor is constitutively active.

Furthermore, the present invention relates to a method of inhibiting anactivation of a monoamine receptor comprising contacting the monoaminereceptor or a system containing the monoamine receptor with an effectiveamount of compound of formula (I), as well as kits for performing thesame. In a preferred embodiment, the compound is selective for the5-HT2A serotonin receptor. In another preferred embodiment, the compoundhas little or substantially no anti-dopaminergic activity. The receptormay be constitutively active or may be activated by an endogenous orexogenous agonistic agent.

Another aspect of the present invention relates to a method of treatinga disease condition associated with a monoamine receptor comprisingadministering to a mammal in need of such treatment an effective amountof a compound of formula (I), and kits for performing the same. Examplesof disease conditions for which such treatment using the compounds ofthe invention, or pharmaceutical compositions comprising them, is usefulinclude, but are not limited to, neuropsychiatric diseases such asschizophrenia and related idiopathic psychoses, depression, anxiety,sleep disorders, appetite disorders, affective disorders such as majordepression, bipolar disorder, and depression with psychotic features,and Tourette's Syndrome. Said compounds may also be beneficial for thetreatment of drug-induced psychoses as well as psychoses secondary toneurodegenerative disorders such as Alzheimer's or Huntington's Disease.The compounds of the invention may also be useful in treatinghypertension, migraine, vasospasm, ischemia and the primary treatmentand secondary prevention of various thrombotic conditions includingmyocardial infarction, thrombotic or ischemic stroke, idiopathic andthrombotic thrombocytopenic purpura, and peripheral vascular disease.

Further provided is a method for identifying a genetic polymorphismpredisposing a subject to being responsive to a compound of formula (I),comprising administering to a subject an effective amount of thecompound; identifying a responsive subject having an ameliorated diseasecondition associated with a monoamine receptor; and identifying agenetic polymorphism in the responsive subject, wherein the geneticpolymorphism predisposes a subject to being responsive to the compound.Also provided are kits for performing the same.

A method for identifying a subject suitable for treatment with thecompound of formula (I) and kits for identifying the same, is alsoprovided. According to the method, the presence of a polymorphism thatpredisposes the subject to being responsive to the compound is detected,wherein the presence of the polymorphism indicates that the subject issuitable for treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing data obtained from a dose response analysis of26HCH17 and ritanserin as 5-HT2A receptor inverse agonists.

FIG. 2 is a graphic representation of in vivo pharmacology data obtainedin mice with2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamidehydrochloride. FIG. 2A shows the effects of this novel antipsychoticagent compound in a head twitch behavioral model; FIG. 2B shows theresults of locomotor experiments; and in FIG. 2C pre-pulse inhibitionstudy results are shown.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

For the purpose of the current disclosure, the following definitionsshall in their entireties be used to define technical terms, and shallalso, in their entireties, be used to define the scope of thecomposition of matter for which protection is sought in the claims.

“Constitutive activity” is defined as the elevated basal activity of areceptor which is independent of the presence of an agonist.Constitutive activity of a receptor may be measured using a number ofdifferent methods, including cellular (e.g., membrane) preparations(see, e.g., Barr & Manning, J. Biol. Chem. 272:32979-87 (1997)),purified reconstituted receptors with or without the associatedG-protein in phospholipid vesicles (Cerione et al., Biochemistry23:4519-25 (1984)), and functional cellular assays (U.S. PatentApplication Ser. No. 60/103,317).

“Agonist” is defined as a compound that increases the activity of areceptor when it contacts the receptor.

An “antagonist” is defined as a compound that competes with an agonistor inverse agonist for binding to a receptor, thereby blocking theaction of an agonist or inverse agonist on the receptor. However, anantagonist (also known as a “neutral” antagonist) has no effect onconstitutive receptor activity.

An “inverse agonist” is defined as a compound that decreases the basalactivity of a receptor (i.e., signalling mediated by the receptor). Suchcompounds are also known as negative antagonists. An inverse agonist isa ligand for a receptor that causes the receptor to adopt an inactivestate relative to a basal state occurring in the absence of any ligand.Thus, while an antagonist can inhibit the activity of an agonist, aninverse agonist is a ligand that can alter the conformation of thereceptor in the absence of an agonist. The concept of an inverse agonisthas been explored by Bond et al. in Nature 374:272 (1995). Morespecifically, Bond et al. have proposed that unliganded β₂-adrenoceptorexists in an equilibrium between an inactive. conformation and aspontaneously active conformation. Agonists are proposed to stabilizethe receptor in an active conformation. Conversely, inverse agonists arebelieved to stabilize an inactive receptor conformation. Thus, while anantagonist manifests its activity by virtue of inhibiting an agonist, aninverse agonist can additionally manifest its activity in the absence ofan agonist by inhibiting the spontaneous conversion of an unligandedreceptor to an active conformation.

The “5-HT2A receptor” is defined as a receptor, having an activitycorresponding to the activity of the human serotonin receptor subtype,which was characterized through molecular cloning and pharmacology asdetailed in Saltzman et al., Biochem. Biophys. Res. Comm. 181:1469-78;and Julius et al., Proc. Natl. Acad. Sci. USA 87:928-932.

The term “subject” refers to an animal, preferably a mammal, mostpreferably a human, who is the object of treatment, observation orexperiment.

“Selective” is defined as a property of a compound whereby an amount ofthe compound sufficient to effect a desired response from a particularreceptor type, subtype, class or subclass with substantially little orno effect upon the activity other receptor types. “Selectivity” or“selective,” as an inverse agonist is understood as a property of acompound of the invention whereby an amount of compound that effectivelyinversely agonises the 5-HT2A receptor, and thereby decreases itsactivity, causes little or no inverse agonistic or antagonistic activityat other, related or unrelated, receptors. In particular, the compoundsof the invention have surprisingly been found not to interact stronglywith other serotonin receptors (5-HT 1A, 1B, 1D, 1E, 1F, 2B, 2C, 4A, 6,and 7) at concentrations where the signalling of the 5-HT2A receptor isstrongly or completely inhibited. Preferably, the compounds of theinvention are also selective with respect to other monoamine-bindingreceptors, such as the dopaminergic, histaminergic, adrenergic andmuscarinic receptors. Compounds that are highly selective for 5-HT2Areceptors may have a beneficial effect in the treatment of psychosis,schizophrenia or similar neuropsychiatric disorders, while avoidingadverse effects associated with drugs hitherto suggested for thispurpose.

EC50 for an agoninst is intended to denote the concentration of acompound needed to achieve 50% of a maximal response seen in R-SAT. Forinverse agonists, EC50 is intended to denote the concentration of acompound needed to achieve 50% inhibition of an R-SAT response frombasal, no compound, levels.

As used herein, “coadministration” of pharmacologically active compoundsrefers to the delivery of two or more separate chemical entities,whether in vitro or in vivo. Coadministration refers to the simultaneousdelivery of separate agents; to the simultaneous delivery of a mixtureof agents; as well as to the delivery of one agent followed by deliveryof a second agent or additional agents. In all cases, agents that arecoadministered are intended to work in conjunction with each other.

“Cyclic organyl groups” are aliphatic, alicyclic groups in which carbonatoms form a ring. In preferred embodiments containing four, five, sixor seven carbon atoms, the ring, as a substituent, is connected eitherdirectly via one of the ring atoms or via one or more appended carbonatoms. Particular examples of such groups include cyclopentyl,cyclohexyl, cycloheptyl, cyclopentylmethyl, cyclohexylmethyl,cyclohexylethyl groups, and the like.

“Straight-chained acyclic organyl groups” are substituent groupsconsisting of a linear arrangement of carbon atoms, where accordinglyeach carbon atom binds a maximum of two other carbon atoms, connectedthrough single, double, or triple bonds. The straight-chained organylgroups may contain none, one, or several multiple bonds, and are, forexample, commonly referred to as alkyl, alkenyl or alkynyl, oralkadienyl groups, respectively. Examples of straight-chained organylgroups include methyl, ethyl, propyl, butyl, pentyl, hexyl, propenyl,butenyl, pentadienyl, propargyl, butynyl.

“Branched acyclic organyl groups” are substituent groups consisting of abranched arrangement of carbon atoms, where accordingly one or morecarbon atoms may bind more than two other carbon atoms, connectedthrough single, double, or triple bonds. The branched organyl groups maycontain none, one, or several multiple bonds. Examples of branchedorganyl groups include iso-propyl, iso-butyl, tert-butyl, methylbutyl,methylbutenyl, methylbutynyl.

“Lower alkoxy groups” are C₁₋₆ cyclic or acyclic organyl groupsconnected, as substituents, via an oxygen atom. Examples of lower alkoxygroups include methoxy, ethoxy, iso-propoxy, butoxy, tert-butoxy.

“Lower alkyl groups” are C₁₋₆ cyclic, straight-chained or branchedaliphatic substituent groups connected via a carbon atom. Examplesinclude methyl, ethyl, propyl, butyl, methylbutyl, cyclopropyl,cyclohexyl, iso-propyl, tert-butyl.

“Lower alkylamino groups” are understood as lower alkyl groupsconnected, as substituents, via a nitrogen atom, which may carry one ortwo lower alkyl groups. Particular examples include methylamino,dimethylamino, iso-propylamino. Optionally, lower aminoalkyl groups mayconsist of 4-6 membered nitrogen-containing rings, such as pyrrolidino.

“Lower aminoalkyl groups” are lower alkyl groups carrying, as asubstituent, an additional amino group. Examples include aminomethyl andaminoethyl.

“Lower hydroxyalkyl groups” are understood as lower alkyl groupscarrying, as a substituent, an additional hydroxy group. Examplesinclude hydroxymethyl, hydroxyethyl, 2-hydroxy-2-propyl, hydroxypentyl.

“Acyl groups” are hydrogen or lower alkyl groups connected, assubstituents, via a carbonyl group. Examples include formyl, acetyl,propanoyl.

“Halo groups” are understood to be fluoro, chloro, bromo, or iodosubstituents, with fluoro and chloro being generally preferred.

“Lower alkylene groups” are straight-chained tethering groups, formingbonds to connect molecular fragments via their terminal carbon atoms.Examples include methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—) or butylene (—(CH₂)₄—) groups.

“Vinylene groups” are ethene-1,2-diyl groups (—CHCH—) having (E) or (Z)configuration.

“Aralkyl groups” are aryl groups connected, as substituents, via a loweralkylene group. The aryl groups of aralkyl groups may be substituted orunsubstituted. Examples include benzyl, substituted benzyl,2-phenylethyl, 3-phenylpropyl, naphthylalkyl.

‘Heteroaralkyl groups’ are understood as heteroaryl groups connected, assubstituents, via a lower alkylene group. The heteroaryl groups ofheteroaralkyl groups may be substituted or unsubstituted. Examplesinclude 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl,pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl, and theirsubstituted as well as benzo-fused analogs.

“Aryl groups” are aromatic, preferably benzenoid or naphthoid, groupsconnected via one of the ring-forming carbon atoms, and optionallycarrying one or more substituents selected from halo, hydroxy, amino,cyano, nitro, alkylamido, acyl, lower alkoxy, lower alkyl, lowerhydroxyalkyl, lower aminoalkyl, lower alkylamino, alkylsulfenyl,alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Preferredaryl groups are phenyl, and, most suitably, substituted phenyl groups,carrying one or two, same or different, of the substituents listedabove. The preferred pattern of substitution is para and/or meta.Representative examples of aryl groups include, but are not limited to,phenyl, 3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl,3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl,dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl,trifluoromethylphenyl.

“Heteroaryl groups” are understood as aromatic, C₂₋₆ cyclic groupscontaining one O or S atom or up to four N atoms, or a combination ofone O or S atom with up to two N atoms, and their substituted as well asbenzo- and pyrido-fused derivatives, preferably connected via one of thering-forming carbon atoms. Heteroaryl groups may carry one or moresubstituents, selected from halo, hydroxy, amino, cyano, nitro,alkylamido, acyl, lower alkoxy, lower alkyl, lower hydroxyalkyl, loweraminoalkyl, lower alkylamino, alkylsulfenyl, alkylsulfinyl,alkylsulfonyl, sulfamoyl, or trifluoromethyl. Preferred heteroarylgroups are five- and six-membered aromatic heterocyclic systems carrying0, 1, or 2 substituents, which may be the same as or different from oneanother, selected from the list above. Representative examples ofheteroaryl groups include, but are not limited to, unsubstituted andmono- or di-substituted derivatives of furan, benzofuran, thiophene,benzothiophene, pyrrole, indole, oxazole, benzoxazole, isoxazole,benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole,benzimidazole, pyrazole, indazole, and tetrazole, which are allpreferred, as well as furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole,1,2,4-thiadiazole, triazole, benzotriazole, pyridine, quionoline,isoquinoline, pyridazine, pyrimidine, purine, pyrazine, pteridine, andtriazine. The most preferred substituents are halo, hydroxy, cyano,lower alkoxy, lower alkyl, lower hydroxyalkyl, lower alkylamino, andlower aminoalkyl.

The present invention provides compounds preferably showing a realtivelyhigh selectivity toward serotonin receptors, particularly, 5-HT2Areceptors, which may have a beneficial effect in the treatment ofneuropsychiatric disorders.

According to one embodiment, the present invention provides compounds ofthe general formula (I):

wherein

Z is

in which

R is a hydrogen, a cyclic or straight-chained or branched acyclicorganyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, oran aralkyl or heteroaralkyl group;

n is 0, 1, or 2;

X₁ is methylene, vinylene, or an NH or N (lower alkyl) group; and

X₂ is methylene, or, when X₁ is methylene or vinylene, X₂ is methyleneor a bond; or when X₁ is methylene, X₂ is O, S, NH, or N(lower alkyl) ora bond;

X

Y₁ is methylene and Y₂ is methylene, vinylene, ethylene, propylene, or abond; or

Y₁ is a bond and Y₂ is vinylene; or

Y₁ is ethylene and Y₂ is O, S, NH, or N(lower alkyl);

Ar₁ and Ar₂ independently are unsubstituted or substituted aryl orheteroaryl groups; and

W is oxygen or sulfur;

or a pharmacologically acceptable salt, ester, or prodrug thereof.

In general, compounds of formula (I) are active at monoamine receptors,specifically serotonin receptors. Preferred compounds share the commonproperty of acting as inverse agonists at the 5-HT2A receptor. Thus,experiments performed on cells transiently expressing the humanphenotype of said receptor have shown that the compounds of generalformula (I) attenuate the signalling of such receptors in the absence ofadditional ligands acting upon the receptor. The compounds have thusbeen found to possess intrinsic activity at this receptor and are ableto attenuate the basal, non-agonist-stimulated, constitutive signallingresponses that the 5-HT2A receptor displays. The observation that thecompunds of general formula (I) are inverse agonists also indicates thatthese compounds have the ability to antagonize the activation of 5-HT2Areceptors that is mediated by endogenous agonists or exogenous syntheticagonist ligands.

In a preferred embodiment, the present invention provides compounds thatpreferably show a relatively high degree of selectivity towards the5-HT2A subtype of serotonin receptors relative to other subtypes of theserotonin (5-HT) family of receptors as well as to other receptors, mostparticularly the monoaminergic G-protein coupled receptors, such asdopamine receptors. In another preferred embodiment, the compounds ofthe present invention act as inverse agonists at the 5-HT2A subtype ofserotonin receptors.

The compounds of general formula (I) may therefore be useful fortreating or alleviating symptoms of disease conditions associated withimpaired function, in particular elevated levels of activity, ofespecially 5-HT2A receptors, whether this impaired function isassociated with improper levels of receptor stimulation or phenotypicalaberrations.

Others have previously hypothesised that certain neuropsychologicaldiseases might be caused by altered levels of constitutive activity ofmonoamine receptors. Such constitutive activity might be modified viacontacting the relevant receptor with a synthetic inverse agonist. Bydirectly testing a large number of centrally acting medicinal compoundswith known clinical activity in neuropsychiatric disease, we determinedthat compounds with antipsychotic efficacy all shared a common molecularproperty. Nearly all of these compounds that are used by psychiatriststo treat psychosis were found to be potent 5-HT2A inverse agonists. Thiscorrelation is compelling evidence that 5-HT2A receptor inverse agonismis a molecular mechanism of antipsychotic efficacy in humans.

Detailed pharmacological characterization of a large number ofantipsychotic compounds in our laboratory revealed that they possessbroad activity at multiple related receptor subtypes. Most of thesecompounds display either agonist, competitive antagonist, or inverseagonist activity at multiple monoaminergic receptor subtypes includingserotoninergic, dopaminergic, adrenergic, muscarinic and histaminergicreceptors. This broad activity is likely responsible for the sedating,hypotensive, and motor side effects of these compounds. It follows thatthe compounds disclosed herein will possess efficacy as, for example,novel antipsychotics, but will have fewer or less severe side effectsthan existing compounds.

The present invention also provides pharmaceutical compositionscomprising an effective amount of a compound of general formula (I).

In a preferred embodiment of the compounds of formula (I), Y₁ ismethylene and Y₂ is a bond, methylene, ethylene, or vinylene, or Y₁ isethylene and Y₂ is O or S, and X₁ is methylene and X₂ is a bond,methylene, O, or S, or X₁ is NH or N(lower alkyl).

In a further preferred embodiment of the compounds of formula (I), Z is

and W is oxygen.

In a more preferred embodiment of the compounds of formula (I), n is 1,Y₁ is methylene, Y₂ is a bond, methylene, ethylene, or vinylene, X₁ ismethylene and X₂ is a bond, or X₁ is NH or N(lower alkyl) and X₂ ismethylene. In a further preferred embodiment of the compounds of formula(I), W is oxygen and Ar₁ and Ar₂ are different aryl or heteroarylgroups, with different mono-substituted phenyl groups being particularlypreferred. Preferably, Ar₁ and Ar₂ are not simultaneously phenyl.

Also preferred compounds of formula (I) are those where Z is 1-(organylor aralkyl)-4-piperidinyl.

In another embodiment, the invention provides preferred compounds ot theformula (II):

in which R^(N) is hydrogen, lower alkyl, aralkyl, or heteroaralkyl;

Ar^(L) is selected from lower alkyl, lower alkoxy and halogen

Ar^(R) is selected from lower alkyl, lower alkoxy and halogen;

k is 1 or 2

and A⁻ is a suitable anion.

According to the invention, a suitable anion may be any anion capable offorming a pharmaceutically acceptable salt of the compound, as describedin further detail below.

The present invention also provides a method of inhibiting an activityof a monoamine receptor. This method comprises contacting a monoaminereceptor or a system containg the monamine receptor, with an effectiveamount of a compound of formula (I). Accoding to one embodiment, themonamine receptor is a serotonin receptor. In a preferred embodiment,the compound is selective for the 5-HT2A receptor subclass. In anotherpreferred embodiment, the compound has little or substantially noactivity to other types of receptors, including other serotonergicreceptors and most particularly, monoaminergic G-protein coupledreceptors, such as dopaminergic receptors.

The system containing the monoamine receptor may, for example, be asubject such as a mammal, non-human primate or a human. The receptor maybe located in the central or peripheral nervous system, blood cells orplatelets.

The system may also be an in vivo or in vitro experimental model, suchas a cell culture model system that expresses a monamine receptor, acell-free extract thereof that contains a monoamine receptor, or apurified receptor. Non-limiting examples of such systems are tissueculture cells expressing the receptor or extracts or lysates thereof.Cells that may be used in the present method include any cells capableof mediating signal transduction via monoamine receptors, expecially the5-HT2A receptor, either via endogenous expression of this receptor(e.g., certain types of neuronal cells lines, for example, nativelyexpress the 5-HT2A receptor), or following transfection of cells withplasmids containing the receptor gene. Such cells are typicallymammalian cells (or other eukaryotic cells, such as insect cells orXenopus oocytes), because cells of lower organisms generally lack theappropriate signal transduction pathways for the present purpose.Examples of suitable cells include: the mouse fibroblast cell line NIH3T3 (ATCC CRL 1658), which responds to transfected 5-HT2A receptors bystimulating growth; RAT 1 cells (Pace et al., Proc. Natl. Acad. Sci. USA88:7031-35 (1991)); and pituitary cells (Vallar et al., Nature330:556-58 (1987)). Other useful mammalian cells for the present methodinclude HEK 293 cells, CHO cells and COS cells.

The invention specifically provides methods of inhibiting an activity ofa native, mutated or modified monoamine receptor. Also provided are kitsfor performing the same. In a preferred embodiment, the activity of thereceptor is a signalling activity. In another preferred embodiment, theactivitiy of the receptor is the constitutive basal activity of thereceptor. Preferrably, the compound is an inverse agonist selective forthe 5-HT2A receptor. Most preferably, the compound has little orsubstantially no activity toward other serotonergic or othermonoaminergic receptors, such as dopaminergic receptors.

In one embodiment, the activity of the receptor is a response, such as asignalling response, to an endogenous agonist, such as 5-HT, or anexogenous agonistic agent, such as a drug or other synthetic ligand. Thecompound of formula (I) preferably acts by inversely agonising orantagonising the receptor.

Furthermore, the present invention relates to a method of inhibiting anactivation of a monoamine receptor comprising contacting the monoaminereceptor, or a system containing the monoamine receptor, with one ormore compounds of the invention. The activation of the receptor may bedue to an exogenous or endogenous agonist agent, or may be theconstitutive activation associated with a native, mutated or modifiedreceptor. The receptor may purified or present in an in vitro or in vivosystem. The receptor may also be present in the central or peripheralnervous system, blood cells or platelets of a nonhuman or human subject.Also provided are kits for performing the same.

In a preferred embodiment, the compound is selective for 5-HT classserotonin receptors, more preferably, the 5-HT2A sublass of serotoninreceptors. In another preferred embodiment, the compound has little orsubstantially no anti-dopaminergic activity.

The present invention provides methods of treating a disease conditionassociated with a monoamine receptor comprising administering to amammal in need of such treatment an effective amount of a compound offormula (I). The invention specifically provides methods for treating oralleviating disease conditions associated with improper function orstimulation of native, as well as mutated or otherwise modified, formsof central serotonin receptors, particularly the 5-HT class of suchreceptors, comprising administration of an effective amount of aselective inverse agonist of the general formula (I) to a host in needof such treatment. Also provided are kits for performing the same.

In a preferred embodiment, the receptor is the 5-HT2A subclass. In oneembodiment, the disease condition is associated with dysfunction of theserotonin receptor. In another embodiment, the disease condition isassociated with activation of the serotonin receptor, preferablyinappropriately elevated or constitutive activation, elevatedserotonergic tone, as well as disease conditions associated withsecondary cellular functions imparied by such pathologies.

Examples of diseases for which such treatment using the compounds of theinvention, or pharmaceutical compositions comprising such compounds, isuseful include, but are not limited to, neuropsychiatric diseases suchschizophrenia and related idiopathic psychoses, anxiety, sleepdisorders, appetite disorders, affective disorders such as majordepression, bipolar disorder, and depression with psychotic features,and Tourette's Syndrome, drug-induced psychoses, psychoses secondary toneurodegenerative disorders such as Alzheimer's or Huntington's Disease.It is anticipated that the compounds of this invention, particularlyselective inverse agonists of 5-HT2A that show little or no activity ondopaminergic receptors, may be especially useful for treatingschizophrenia. Treament using the compounds of the invention may also beuseful in treating migraine, vasospasm, hypertension, various thromboticconditions including myocardial infarction, thrombotic or ischemicstroke, idiopathic and thrombotic thrombocytopenic purpura, andperipheral vascular disease.

In a further embodiment the present invention provides methods fortreating or alleviating a disease condition associated with improperfunction, dysfunction, or stimulation of native, as well as mutated orotherwise modified, forms of central or peripheral monoamine receptors,such methods comprising administration of an effective amount of acompound of the general formula (I) to a host in need of such treatment.Preferably the monamine receptor is serotonin receptor in the peripheralnervous system, blood or platelets; more preferably a 5-HT2A subclassreceptor. In additional embodiments, the disease condition is associatedwith increased activity or activation of a serotonin receptor. Alsoprovided are kits for performing the same.

The present invention also pertains to the field of predictive medicinein which pharmacogenomics is used for prognostic (predictive) purposes.Pharmacogenomics deals with clinically significant hereditary variationsin the response to drugs due to altered drug disposition and abnormalaction in affected persons. See e.g., Eichelbaum, Clin Exp Pharmacol.Physiol., 23:983-985 (1996), and Linder, Clin. Chem. 43:254-66 (1997).In general, two types of pharmacogenetic conditions can bedifferentiated: genetic conditions transmitted as a single factoraltering the way drugs act on the body (altered drug action), andgenetic conditions transmitted as single factors altering the way thebody acts on drugs (altered drug metabolism). These pharmacogeneticconditions can occur as naturally occurring polymorphisms.

One pharmacogenomics approach to identifying genes that predict drugresponse, known as “a genome-wide association,” relies primarily on ahigh-resolution map of the human genome consisting of already knowngene-related markers (e.g., a “bi-allelic” gene marker map that consistsof 60,000-100,000 polymorphic or variable sites on the human genome,each of which has two variants). Such a high-resolution genetic map canbe compared to a map of the genome of each of a statisticallysignificant number of patients taking part in a Phase II/III drug trialto identify markers associated with a particular observed drug responseor side effect. Alternatively, such a high-resolution map can begenerated from a combination of some ten-million known single nucleotidepolymorphisms (SNPs) in the human genome. As used herein, a “SNP” is acommon alteration that occurs in a single nucleotide base in a stretchof DNA. For example, a SNP may occur once per every 1,000 bases of DNA.A SNP may be involved in a disease process; however, the vast majoritymay not be disease-associated. Given a genetic map based on theoccurrence of such SNPs, individuals can be grouped into geneticcategories depending on a particular pattern of SNPs in their individualgenome. In such a manner, treatment regimens can be tailored to groupsof genetically similar individuals, taking into account traits that maybe common among such genetically similar individuals.

Alternatively, a method termed the “candidate gene approach” can beutilized to identify genes that predict drug response. According to thismethod, if a gene that encodes a drug's target is known (e.g., a proteinor a receptor of the present invention), all common variants of thatgene can be fairly easily identified in the population and it can bedetermined if having one version of the gene versus another isassociated with a particular drug response.

Alternatively, a method termed the “gene expression profiling”, can beutilized to identify genes that predict drug response. For example, thegene expression of an animal dosed with a drug (e.g., a molecule ormodulator of the present invention) can give an indication whether genepathways related to toxicity have been turned on.

Information generated from more than one of the above pharmacogenomicsapproaches can be used to determine appropriate dosage and treatmentregimens for prophylactic or therapeutic treatment of an individual.This knowledge, when applied to dosing or drug selection, can avoidadverse reactions or therapeutic failure and thus enhance therapeutic orprophylactic efficiency when treating a subject with a molecule ormodulator of the invention, such as a modulator identified by one of theexemplary screening assays described herein. As we have describedpreviously, this approach can also be used to identify novel candidatereceptor or other genes suitable for further pharmacologicalcharacterization in vitro and in vivo.

Accordingly, the present invention also provides methods and kits foridentifying a genetic polymorphism predisposing a subject to beingresponsive to a compound described herein. The method comprisesadministering to a subject an effective amount of a compound;identifying a responsive subject having an ameliorated disease conditionassociated with a monamine receptor; and identifying a geneticpolymorphism in the responsive subject, wherein the genetic polymorphismpredisposes a subject to being responsive to the compound. It isanticipated that this method may be useful both for predicting whichindividuals are responsive to therapeutic effects of a compound and alsofor predicting those likely to experience adverse side effect responses.This approach may be useful for identifying, for example, polymorphismsin a serotonin receptor that lead to constitutive activation and arethus amenable to inverse agonist therapy. In addition, this method maybe useful for identifying polymorphisms that lead to altered drugmetabolism whereby toxic byproducts are generated in the body. Such amechanism has been implicated in the rare, but potentially lifethreatening side effects of the atypical antipsychotic, clozapine.

In a related embodiment, a method for identifying a subject suitable fortreatment with a compound of the present invention is provided.According to the method, the presence of a polymorphism that predisposesthe subject to being responsive to the compound is detected, thepresence of the polymorphism indicating that the subject is suitable fortreatment. Also provided are kits for performing the same.

The compounds of this invention preferably show selective inverseagonist activity towards the 5-HT2A receptor. Such activity is definedby an ability of the ligand to attenuate or abolish the constitutivesignaling activity of this receptor. Selectivity in the present contextis understood as a property of a compound of the invention whereby anamount of compound that effectively inversely agonizes the 5-HT2Areceptor and thereby decreases its activity causes little or no inverseagonistic or antagonistic activity at other, related or unrelated,receptors. In particular, the compounds of the invention havesurprisingly been found not to interact strongly with other serotoninreceptors (5-HT 1A, 1B, 1D, 1E, 1F, 2B, 2C, 4A, 6, and 7) atconcentrations where the signaling of the 5-HT2A receptor is strongly orcompletely inhibited. Preferably, the compounds of the invention arealso selective with respect to other monoamine-binding receptors, suchas the dopaminergic, histaminergic, adrenergic and muscarinic receptors.

A particularly preferred embodiment of this invention includes:

N-(1-(1-methylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(2,2-dimethylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-pentylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-hexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-cyclohexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-cyclopentylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-cyclobutylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-cyclopropylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(cyclopentylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(cyclobutylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(cyclopropylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(2-hydroxyethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(3-hydroxypropyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-((4-Methylphenyl)methyl)-N-(piperidin-4-yl)-N′-phenylmethylcarbamide;

N-((4-Methylphenyl)methyl)-N-(1-(2-methylpropyl)piperidin-4-yl)-N′-phenylmethylcarbamide;

N-(1-((2-Bromophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide;

N-(1-((4-Hydroxy-3-methoxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide;

N-(1-((5-Ethylthien-2-yl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide;

N-(1-(Imidazol-2-ylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide;

N-(1-(Cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide;

N-(1-((4-Fluorophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide;

N-((4-Methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((4-Methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-4-methoxyphenylacetamide;

N-(1-Ethylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-((4-Methylphenyl)methyl)-N-(1-propylpiperidin-4-yl)-4-methoxyphenylacetamide;

N-(1-Butylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(3,3-Dimethylbutyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-(Cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-((4-Methylphenyl)methyl)-N-(1-(2-methylpropyl)piperidin-4-yl)-4-methoxyphenylacetamide;

N-((4-Methylphenyl)methyl)-N-(1-((4-methylphenyl)methyl)piperidin-4-yl)-4-methoxyphenylacetamide;

N-(1-((4-Hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(1-((2-Hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;

N-(3-Phenylpropyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-(2-Phenylethyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((2-Methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((2-Chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((3,4-Di-methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((4-Fluorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((2,4-Di-chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((3-Methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-((3-Bromophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;

N-(1-(Phenylmethyl)piperidin-4-yl)-N-(3-phenyl-2-propen-1-yl)-4-methoxyphenylacetamide;

N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-phenylacetamide;

N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-3-phenylpropionamide;

N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-(phenylthio)acetamide;

N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-phenoxyacetamide;

N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-(4-chlorophenoxy)acetamide;

N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-3-methoxyphenylacetamide;

N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-4-fluorophenylacetamide;

N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-2,5-di-methoxyphenylacetamide;

N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-4-chlorophenylacetamide;

N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-N′-phenylmethylcarbamide;

N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-4-methoxyphenylacetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(piperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-ethylpiperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-isopropylpiperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-(4-chlorobenzyl)-N-(piperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-cyclopentylpiperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-isopropylpiperidin-4-yl)acetamide;

2-(phenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-fluorophenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Methoxyphenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Trifluoromethylphenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Fluorophenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Methoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(phenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Trifluoromethylphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-trifluoromethylphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin4-yl)acetamide;

2-Phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-trifluoromethylphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;

2-Phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;

2-(4methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(4-chloromethyl-2-thiazolylmethyl)piperidin-4-yl]acetamide;

2-(4 methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3(1,3dihydro-2H-benzimidazol-2-on-1-yl)propyl]piperidin-4-yl}acetamide;

2-(4-methoxyphenyl)-N-(2-4(fluorophenyl)ethyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-[2-(2,5-dimethoxyphenyl)ethyl]-N-(1-methylpiperidin-4yl)acetamide;

2-(4-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-[2-(3-chlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-[2-(3-fluorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-ethoxyphenyl)-N-[2-(4-fluorophenethyl]-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-ethoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2-hydroxyethoxy)ethyl]piperidin-4-yl}acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-((2-chloro-5-thienyl)methyl)piperidin-4-yl]acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-(imidazolidinon-1-yl)ethyl)piperidin-4-yl]acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2,4(1H,3H)quinazolinedion-3-yl)ethyl]piperidin-4-yl}acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(1,3-dioxolan-2-yl)ethyl]piperidin-4-yl}acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(3-indolyl)ethyl]piperidin-4-yl}acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(1,2,4-triazol-1-yl)propyl]piperidin-4-yl}acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-benzofurazanylmethyl)piperidin-4-yl]acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-chlorobenzo[b]thien-3-ylmethyl)piperidin-4-yl]acetamide;

2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-phenyl-1,2,4-oxadiazol-3-ylmethyl)piperidin-4-yl]acetamide;

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-isopropylpiperidin-4-yl)-acetamide;

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperidin-4-yl)-acetamide;

2-Phenyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide,2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclopentylpiperidin-4-yl)-acetamide;

2-(4-Fluorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-(2-hydroxyethyl)-piperidin-4-yl)-acetamide;

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-yl)-acetamide;

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-yl)-acetamide;

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide;

N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′-benzyl-carbamide;

N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′-phenyl-carbamide;

N-Phenethyl-N-(1-methylpiperidin-4-yl)-N′-benzyl-carbamide;

2-Phenyl-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Trifluoromethylphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Fluorophenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Methoxyphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Methylphenyl)-N-(4-chlorobenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

2-(4-Hydroxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;

N-Phenethyl-N-(1-methylpiperidin-4-yl)-N′-phenyl-carbamide;

N-(3-Phenylpropyl)-N-(1-methylpiperidin-4-yl)-N′-benzyl-carbamide;

N-(3-Phenylpropyl)-N-(1-methylpiperidin-4-yl)-N′-phenyl-carbamide;

2-(4-Methoxyphenyl)-2,2-ethylene-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Methoxyphenyl)-N-alpha-methylbenzyl-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-aza-bicyclo[3.2.1]octen-3-yl)-acetamide;

2-Phenyl-2-ethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

N-Phenethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-amine;

2-(4-Methoxyphenyl)-N-(1-indanyl)-N-(1-methylpiperidin-4-yl)acetamide;

N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-methoxybenzyl)-carbamide;

2-(3,4-dimethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(3,4-Methylenedioxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-acetamide;

N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′-phenethyl-carbamide;

N-Phenethyl-N-(1-methylpiperidin-4-yl)-N′-phenethyl-carbamide;

N-(4-Methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-N′-(4-methoxybenzyl)-carbamide;

2-(4-Ethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-i-Propoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-t-Butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Butoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-Propoxyphenyl)-N-(4-flourobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

2-(4-i-Propoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;

and,2-(4-t-Butoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide.

Suitable pharmaceutically acceptable salts of the compounds of thisinvention include acid addition salts that may, for example, be formedby mixing a solution of the compound according to the invention with asolution of a pharmaceutically acceptable acid such as hydrochloricacid, sulphuric acid, fumaric acid, maleic acid, succinic acid, aceticacid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Examples of pharmaceutically acceptable salts include theacetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium, carbonate, chloride, clavulanate, citrate,dihydrochloride, fumarate, gluconate, glutamate, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, maleate, mandelate, mesylate, methylbromide,methylnitrate, methylsulfate, nitrate, N-methylglucamine ammonium salt,oleate, oxalate, phosphate/diphosphate, salicylate, stearate, sulfate,succinate, tannate, tartrate, tosylate, triethiodide and valerate salt.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs are inactivederivatives of the compounds of this invention that are readilyconvertible in vivo into the required compound. Conventional proceduresfor the selection and preparation of suitable prodrug derivatives aredescribed, for example, in Design of Prodrugs, (ed. H. Bundgaard,Elsevier, 1985). Metabolites of these compounds include active speciesthat are produced upon introduction of compounds of this invention intothe biological milieu.

Where the compounds according to the invention have at least one chiralcenter, they may exist as a racemate or as enantiomers. It should benoted that all such isomers and mixtures thereof are included in thescope of the present invention. Furthermore, some of the crystallineforms for compounds of the present invention may exist as polymorphs andas such are intended to be included in the present invention. Inaddition, some of the compounds of the present invention may formsolvates with water (i.e., hydrates) or common organic solvents. Suchsolvates are also included in the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixtures of stereoisomers, such isomers maybe separated by conventional techniques such as preparative chiralchromatography. The compounds may be prepared in racemic form orindividual enantiomers may be prepared by stereoselective synthesis orby resolution. The compounds may be resolved into their componentenantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation with an optically active acid,such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides followed by chromatographicseparation and removal of the chiral auxiliary.

Compounds of the present invention may be administered in any of theforegoing compositions and according to dosage regimens established inthe art whenever specific pharmacological modification of the activityof monoamine receptors is required.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of the invention together with apharmaceutically acceptable diluent or excipient. Preferably suchcompositions are in unit dosage forms such as tablets, pills, capsules(including sustained-release or delayed-release formulations), powders,granules, elixirs, tinctures, syrups and emulsions, sterile parenteralsolutions or suspensions, aerosol or liquid sprays, drops, ampoules,auto-injector devices or suppositories; for oral, parenteral (e.g.,intravenous, intramuscular or subcutaneous), intranasal, sublingual orrectal administration, or for administration by inhalation orinsufflation, and may be formulated in an appropriate manner and inaccordance with accepted practices such as those disclosed inRemington's Pharmaceutical Sciences, (Gennaro, ed., Mack Publishing Co.,Easton Pa., 1990, herein incorportated by reference). Alternatively, thecompositions may be in sustained-release form suitable for once-weeklyor once-monthly administration; for example, an insoluble salt of theactive compound, such as the decanoate salt, may be adapted to provide adepot preparation for intramuscular injection. The present inventionalso contemplates providing suitable topical formulations foradministration to, e.g., eye or skin or mucosa.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents, flavoring agentsand coloring agents can also be incorporated into the mixture. Suitablebinders include, without limitation, starch, gelatin, natural sugarssuch as glucose or beta-lactose, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include, without limitation, sodium oleate, sodium stearate,magnesium stearate, sodium benzoate, sodium acetate, sodium chloride andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.

For preparing solid compositions such as tablets, the active ingredientis mixed with a suitable pharmaceutical excipient such as the onesdescribed above and other pharmaceutical diluents, e.g., water, to forma solid preformulation composition containing a homogeneous mixture of acompound of the present invention or a pharmaceutically acceptable saltthereof. By the term “homogeneous” is meant that the active ingredientis dispersed evenly throughout the composition so that the compositionmay be readily subdivided into equally effective unit dosage forms suchas tablets, pills and capsules. The solid preformulation composition maythen be subdivided into unit dosage forms of the type described abovecontaining from 0.1 to about 50 mg of the active ingredient of thepresent invention. The tablets or pills of the present composition maybe coated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner core containing the active compound and an outer layeras a coating surrounding the core. The outer coating may be an entericlayer that serves to resist disintegration in the stomach and permitsthe inner core to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings including a number of polymeric acids and mixtures of polymericacids with conventional materials such as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the present compositions may be incorporatedfor administration orally or by injection include aqueous solutions,suitably flavored syrups, aqueous or oil suspensions, and flavoredemulsions with edible oils such as cottonseed oil, sesame oil, coconutoil or peanut oil, as well as elixirs and similar pharmaceuticalcarriers. Suitable dispersing or suspending agents for aqueoussuspensions include synthetic and natural gums such as tragacanth,acacia, alginate, dextran, sodium carboxymethylcellulose, gelatin,methylcellulose or polyvinylpyrrolidone. Other dispersing agents thatmay be employed include glycerin and the like. For parenteraladministration, sterile suspensions and solutions are desired. Isotonicpreparations that generally contain suitable preservatives are employedwhen intravenous administration is desired. The compositions can also beformulated as an ophthalmic solution or suspension formation, i.e., eyedrops, for ocular administration.

Consequently, the present invention also relates to a method ofalleviating or treating a disease condition in which modification ofmonoamine receptor activity, in particular 5-HT2A serotonergic receptoractivity, has a beneficial effect by administering a therapeuticallyeffective amount of a compound of the present invention to a subject inneed of such treatment. Such diseases or conditions may, for instancearise from inappropriate stimulation or activation of serotonergicreceptors. It is anticipated that by using compounds that are selectivefor a particular serotonin receptor subtype, in particular 5-HT2A, theproblems with adverse side effects observed with the known antipsychoticdrugs, such as extrapyramidal effects, may be avoided substantially.

The term “therapeutically effective amount” as used herein means anamount of an active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease being treated.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses, for example, two, three or four times daily. Furthermore,compounds of the present invention may be administered in intranasalform via topical use of suitable intranasal vehicles, via transdermalroutes, using those forms of transdermal skin patches well known topersons skilled in the art, by implantable pumps; or by any othersuitable means of administration. To be administered in the form of atransdermal delivery system, for example, the dosage administrationwill, of course, be continuous rather than intermittent throughout thedosage regimen.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound employed. A physician or veterinarian of ordinary skill canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the disease ordisorder that is being treated.

The daily dosage of the products may be varied over a wide range fromabout 0.01 mg to about 100 mg per adult human per day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0or 50.0 mg of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. A unit dose typically containsfrom about 0.001 mg to about 50 mg of the active ingredient, preferablyfrom about 1 mg to about 10 mg of active ingredient. An effective amountof the drug is ordinarily supplied at a dosage level of from about0.0001 mg/kg to about 25 mg/kg of body weight per day. Preferably, therange is from about 0.001 to 10 mg/kg of body weight per day, andespecially from about 0.001 mg/kg to 1 mg/kg of body weight per day.

Compounds according to the present invention may be used alone atappropriate dosages defined by routine testing in order to obtainoptimal pharmacological effect on a monoaminergic receptor, inparticular the 5-HT2A serotonergic receptor subtype, while minimizingany potential toxic or otherwise unwanted effects. In addition,co-administration or sequential administration of other agents thatimprove the effect of the compound may, in some cases, be desirable.

The pharmacological properties and the selectivity of the compounds ofthis invention for specific serotonergic receptor subtypes may bedemonstrated by a number of different assay methods using recombinantreceptor subtypes, preferably of the human receptors if these areavailable, e.g. conventional second messenger or binding assays. Aparticularly convenient functional assay system is the receptorselection and amplification assay disclosed in U.S. Pat. No. 5,707,798,which describes a method of screening for bioactive compounds byutilizing the ability of cells transfected with receptor DNA, e.g.,coding for the different serotonergic subtypes, to amplify in thepresence of a ligand of the receptor. Cell amplification is detected asincreased levels of a marker also expressed by the cells.

Methods of Preparation

The compounds in accordance with the present invention may besynthesized by methods described below, or by modification of thesemethods. Ways of modifying the methodology include, among others,temperature, solvent, reagents etc, and will be obvious to those skilledin the art.

For instance, compounds of the formula C may be synthesized from thecorresponding ketone A by reductive amination utilizing any primaryamine. The reaction is conveniently carried out by stirring thereactants in an inert solvent such as methanol or ethanol containingacetic acid. As reducing agent NaBH₄, NaCNBH₃, BH₃.pyridine or anyrelated reagent may be used including solid-supported reagents. Thereaction is typically carried out at room temperature. The ketone A, asexemplified by the piperidone, may be chosen from a list of compoundscorresponding to the Z-group listed in formula (I). The ketones caneither be obtained commercially or synthesized by methodology disclosedin Lowe et al. J. Med. Chem. 37: 2831-40 (1994); Carroll et al. J. Med.Chem. 35:2184-91 (1992); or Rubiralta et al. Piperidine—Structure,Perparation, Reactivity and Synthetic Applications of Piperidine and itsDerivatives. (Studies in Organic Chemistry 43, Elsevier, Amsterdam,1991). The protecting group P includes groups such as those described inT. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry,3. Ed. John Wiley & Sons, 1999, and they should be chosen in such a way,that they are stable to the reaction conditions applied and readilyremoved at a convenient stage using methodology known from the art.Typical protecting groups are N-Boc, N-Cbz, N-Bn.

Alternatively, the amine C can be synthesized from the primary amine Bby reductive amination with any aldehyde. The reaction is convenientlycarried out by stirring the reactants in an inert solvent such asmethanol or ethanol containing acetic acid. As reducing agent NaBH₄,NaCNBH₃, BH₃.pyridine or any related reagent may be used includingsolid-supported reagents. The reaction is typically carried out at roomtemperature. The primary amine B, as exemplified by the4-aminopiperidine, may be chosen from a list of compounds correspondingto the Z-groups listed in formula (1). The amines can either be obtainedcommercially or synthesized from the corresponding ketones. Theprotecting group P may be chosen as stated above.

Alternatively, the amine C can be synthesized from the primary amine Bby alkylation with any alkylating agent (R-L₁). The leaving group L₁ issuitably a halogen atom, e.g., bromine or iodine, or a sulfonate, e.g.tosylate or mesylate, or another leaving group favoring the reaction.The reaction is conveniently carried out by stirring the reagents underbasic conditions in an inert solvent, e.g., diisopropylethylamine inacetonitrile, or K₂CO₃ in N,N-dimethylformamide. The reaction istypically carried out at temperatures between room temperature and 80°C. The primary amine B, as exemplified by the 4-aminopiperidine, may bechosen from a list of compounds corresponding to the Z-groups listed informula (I). The amines can either be obtained commercially orsynthesized from the corresponding ketones. The protecting group P maybe chosen as stated above.

Wherein R and R* are defined in agreement with formula (I), and Prepresents a suitable protecting group, and L₁ represents a suitableleaving group.

The secondary amine C may be acylated using any isocyanate orisothiocyanate (Q₁-N═C═W) to give the corresponding ureas or thioureasD. The reaction is typically carried out by stirring the reactants,using an excess of isocyanate or isothiocyanate in an inert solvent,e.g., dichloromethane at a temperature between 0° C. and roomtemperature and under dry conditions. The amine C may also be acylatedusing any carboxylic acid halide (Q₂COX), e.g., chloride, or carboxylicanhydride ((Q₂C═O)₂O) to give amides of the general structure E. Thereaction is typically carried out using an excess of the acylating agentand a suitable base, e.g., triethylamine or diisopropylethylamine in aninert solvent, e.g., dichloromethane, at a temperature between 0° C. androom temperature and under dry conditions. As an alternative to thecarboxylic acid halides and carboxylic acid anhydrides, the amine C maybe acylated using a carboxylic acid (Q₂COOH) and a suitable couplingreagent e.g. DCC or EDCI. The reaction is typically carried out using anexcess of the acylating agent and the coupling reagent in an inertsolvent, e.g., dichloromethane at a temperature between 0° C. and roomtemperature and under dry conditions. The compounds of the generalstructure (E) may be converted into the corresponding thioamides usingmethodology disclosed in Varma et al., Org. Lett. 1: 697-700 (1999);Cherkasov et al. Tetrahedron 41:2567 (1985); or Scheibye et al, Bull.Soc. Chim. Belg. 87:229 (1978).

Wherein R, Q₁, Q₂, and W are defined in agreement with formula (I), Prepresents a suitable protecting group, and X represents a halide.

The substituent G on the ring nitrogen can be introduced by a two stepprocedure. First, the protecting group on the urea D or the amide E isremoved using well-known methods. For example, the N-Boc group isremoved by treating the protected compound with 4 M HCl in dioxane ortrifluoroacetic acid in dichloromethane. Second, the secondary aminesobtained from D and E can be alkylated by reductive amination using anyaldehyde (T-CHO). The reaction is conveniently carried out by stirringthe reactants in an inert solvent such as methanol or ethanol. As areducing agent, solid-supported borohydride, NaH₄, NaCNBH₃, BH₃.pyridineor any related reagent may be used, including solid-supported reagents.The reaction is typically carried out at room temperature.

Alternatively, the compounds F and G can be synthesized from thesecondary amine obtained from D or E as described above by alkylationwith any alkylating agent (T-L₁). The leaving group L₁ is suitably ahalogen atom, e.g., bromine or iodine, or a sulfonate, e.g., tosylate ormesylate, or another leaving group favoring the reaction. The reactionis conveniently carried out by stirring the reagents under basicconditions in an inert solvent, for example diisopropylethylamine inacetonitrile, or K₂CO₃ in N,N-dimethylformamide. The reaction istypically carried out at temperatures between room temperature and 80°C.

Alternatively, the T-group can be introduced in the first step of thesynthetic sequence leading to the compounds in accordance with thepresent invention by N-alkylation of compound H with any alkylatingagent (T-L₁). The leaving group L₁ is suitably a halogen atom, e.g.,bromine or iodine, or a sulfonate, e.g., tosylate or mesylate, oranother leaving group favoring the reaction. The reaction isconveniently carried out by stirring the reagent under basic conditionsin an inert solvent, e.g., diisopropylethylamine in acetonitrile, orK₂CO₃ in N,N-dimethylformamide. The reaction is typically carried out attemperatures between room temperature and 80° C. The secondary amine H,as exemplified by 4-piperidone, may be chosen from a list of compoundscorresponding to the Z-groups listed in formula (I). The amines caneither be obtained commercially or synthesized from methodologydisclosed in Lowe et al., J. Med. Chem. 37:2831-40 (1994); and Carrollet al., J. Med. Chem. 35:2184-91 (1992).

Alternatively, compounds of the general structure J may be synthesizedstarting from K using the method disclosed in: Kuehne et al., J. Org.Chem. 56:2701 (1991); and Kuehne et al., J. Org. Chem. (1991), 56:513.

wherein R, Q₁, Q₂, W, and T are defined in agreement with formula (I),and L₁ is a suitable leaving group.

In general, during any of the processes for preparation of the compoundsof the present invention, it may be necessary and/or desirable toprotect sensitive or reactive groups on any of the molecules concerned.This may be achieved by means of conventional protecting groups, such asthose described in Protective Groups in Organic Chemistry (ed. J. F. W.McOmie, Plenum Press, 1973); and Greene & Wuts, Protective Groups inOrganic Synthesis, John Wiley & Sons, 1991. The protecting groups may beremoved at a convenient subsequent stage using methods known from theart.

EXAMPLES

The invention is disclosed in further detail in the following examplesthat are not in any way intended to limit the scope of the invention asclaimed.

General LC-MS procedure for Examples 1-41: All spectra were obtainedusing an HP1100 LC/MSD-instrument. A setup with a binary pump,autosampler, column oven, diode array detecter, and electrosprayionization interface was used. A reversed phase column (C18 Luna 3 mmparticle size, 7.5 cm×4.6 mm ID) with a guard cartridge system was used.The column was maintained at a temperature of 30° C. The mobile phasewas acetonitrile/8 mM aqueous ammonium acetate. A 15 minute gradientprogram was used, starting at 70% acetonitrile, over 12 minutes to 95%acetonitrile, over 1 minute back to 70% acetonitrile, where it stayedfor 2 minutes. The flow rate was 0.6 ml/min. The tr values reported inthe specific examples. below were obtained using this procedure.

Example 1N-((4-Methylphenyl)methyl)-N-(piperidin-4-yl)-N′-phenylmethylcarbamide(26HCH65)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml)followed by NaCNBH₃ in methanol (0.3 M, 30 ml). The resulting solutionwas stirred at room temperature. After 20 h, water (5 ml) was added, andthe mixture was stirred for 1 h before it was concentrated. Flashchromatography in dichloromethane:methanol 10:1 gave tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4 g,98%. To a solution of tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate (800 mg, 2.63mmol) in dry dichloromethane (20 ml) was added benzylisocyanate (0.65ml, 5.26 mmol). The solution was stirred at room temperature. After 48h, an excess of 2-dimethylaminoethylamine was added. The mixture wasstirred for another 24 h, before it was concentrated. The resultingsolid was redissolved in dichloromethane (20 ml), sequentially washedwith HCl (0.2 N, 3×30 ml), and water (20 ml), dried (Na₂SO₄), filteredand concentrated. Flash chromatography in dichloromethane:methanol 10:1gaveN-((4-methylphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-N′-phenylmethylcarbamide(760 mg, 66%), which was dissolved in diethyl ether (5 ml). HCl (4 M) indioxane (3 ml) was added, and the solution was stirred at roomtemperature for 60min, then concentrated. The resulting oil wasredissolved in a mixture of dichloromethane and diethyl ether (4:1). Theorganic layer was extracted with HCl (0.2 M, 3×20 ml). The combinedaqueous layers were treated with NaOH (0.2 M) until basic (pH>8), thenextracted with dichloromethane (3×20 ml). The combined organic layerswere dried (Na₂SO₄), filtered, and concentrated to give the titlecompound. Yield: 406 mg, 70%; ¹³C-NMR (CDCl₃): δ 21.3, 31.6, 45.0, 45.9,46.4, 53.0, 126.3, 127.2, 127.4, 128.6, 129.8, 135.3, 137.4, 139.7,158.5.

Example 2N-((4-Methylphenyl)methyl)-N-(1-(2-methylpropyl)piperidin-4-yl)-N′-phenylmethylcarbamide(26HCH66-02)

The product from example 1 above (20 mg, 0.06 mmol) was dissolved inabs. ethanol (2 ml). 2-Methylpropionaldehyde (0.08 ml, 0.6 mmol) wasadded followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin;Aldrich 32,864-2). The mixture was shaken at room temperature. After 48h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol)was added to the organic solution. After 24 h, the mixture wasconcentrated and redissolved in methanol (2 ml). The solution was addedon to a column carrying strongly acidic cation exchange resin (0.3mmol/g resin), which was washed with methanol (3×6 ml), and eluted with10% NH₃ in methanol, and concentrated to give the title compound. IR:1640, 1185, 1110 cm⁻¹; LC-MS: (M+H)⁺ 394.2, t_(r) 5.60 min.

Example 3N-(1-((2-Bromophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide(26HCH66-03)

The product from example 1 above (20 mg, 0.06 mmol) was dissolved inabs. ethanol (2 ml). 2-Bromobenzaldehyde (0.07 ml, 0.6 mmol) was addedfollowed by solid-supported borohydride (150 mg, 2.5 mmol/g resin;Aldrich 32,864-2). The mixture was shaken at room temperature. After 48h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol)was added to the organic solution. After 24 h, the mixture wasconcentrated and redissolved in methanol (2 ml). The solution was addedon to a column carrying strongly acidic cation exchange resin (0.3mmol/g resin), which was washed with methanol (3×6 ml), and eluted with10% NH₃ in methanol, and concentrated to give the title compound. IR:1635, 1180, 1110 cm⁻¹; LC-MS: (M+H)⁺ 506.1, t_(r) 8.37 min.

Example 4N-(1-((4-Hydroxy-3-methoxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide(26HCH66-04)

The product from example 1 above (20 mg, 0.06 mmol) was dissolved inabs. ethanol (2 ml). 4-Hydroxy-3-methoxybenzaldehyde (91 mg, 0.6 mmol)was added followed by solid-supported borohydride (150 mg, 2.5 mmol/gresin; Aldrich 32,864-2). The mixture was shaken at room temperature.After 48 h, the resin was filtered off and acetic anhydride (0.02 ml,0.2 mmol) was added to the organic solution. After 24 h, the mixture wasconcentrated and redissolved in methanol (2 ml). The solution was addedon to a column carrying strongly acidic cation exchange resin (0.3mmol/g resin), which was washed with methanol (3×6 ml), and eluted with10% NH₃ in methanol, and concentrated to give the title compound.¹³C-NMR (CD₃OD, selected): δ 19.9, 55.4, 126.5, 127.0, 128.1, 129.0,140.3, 148.0, 148.1, 158.8.

Example 5N-(1-((5-Ethylthien-2-yl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide(26HCH66-05)

The product from example 1 above (20 mg, 0.06 mmol) was dissolved inabs. ethanol (2 ml). 5-Ethyl-2-thiophencarboxaldehyde (84 mg, 0.6 mmol)was added followed by solid-supported borohydride (150 mg, 2.5 mmol/gresin; Aldrich 32,864-2). The mixture was shaken at room temperature.After 48 h, the resin was filtered off and acetic anhydride (0.02 ml,0.2 mmol) was added to the organic solution. After 24 h, the mixture wasconcentrated and redissolved in methanol (2 ml). The solution was addedon to a column carrying strongly acidic cation exchange resin (0.3mmol/g resin), which was washed with methanol (3×6 ml), and eluted with10% NH₃ in methanol, and concentrated to give the title compound. IR:1640, 1185, 1110, 805, 700, 620 cm⁻¹; LC-MS: (M+H)⁺ 462.3, t_(r) 7.52min.

Example 6N-(1-(Imidazol-2-ylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide(26HCH66-06)

The product from example 1 above (20 mg, 0.06 mmol) was dissolved inabs. ethanol (2 ml). Imidazole-2-carboxaldehyde (58 mg, 0.6 mmol) wasadded followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin;Aldrich 32,864-2). The mixture was shaken at room temperature. After 48h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol)was added to the organic solution. After 24 h, the mixture wasconcentrated and redissolved in methanol (2 ml). The solution was addedon to a column carrying strongly acidic cation exchange resin (0.3mmol/g resin), which was washed with methanol (3×6 ml), and eluted with10% NH₃ in methanol, and concentrated to give the title compound. IR:1620, 1190, 1100, 805, 700, 620 cm⁻¹; LC-MS: (M+H)⁺ 418.2, t_(r) 2.05min.

Example 7N-(1-(Cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide(26HCH66-09)

The product from example 1 above (20 mg, 0.06 mmol) was dissolved inabs. ethanol (2 ml). Cyclohexanecarboxaldehyde (67 mg, 0.6 mmol) wasadded followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin;Aldrich 32,864-2). The mixture was shaken at room temperature. After 48h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol)was added to the organic solution. After 24 h, the mixture wasconcentrated and redissolved in methanol (2 ml). The solution was addedon to a column carrying strongly acidic cation exchange resin (0.3mmol/g resin), which was washed with methanol (3×6 ml), and eluted with10% NH₃ in methanol, and concentrated to give the title compound. IR:1635, 1175, 1100, 805, 695, 620 cm⁻¹; LC-MS: (M+H)⁺ 434.4, t_(r) 7.44min.

Example 8N-(1-((4-Fluorophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide(26HCH66-10)

The product from example 1 above (20 mg, 0.06 mmol) was dissolved inabs. ethanol (2 ml). 4-Fluorobenzaldehyde (0.08 ml, 0.6 mmol) was addedfollowed by solid-supported borohydride (150 mg, 2.5 mmol/g resin;Aldrich 32,864-2). The mixture was shaken at room temperature. After 48h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol)was added to the organic solution. After 24 h, the mixture wasconcentrated and redissolved in methanol (2 ml). The solution was addedon to a column carrying strongly acidic cation exchange resin (0.3mmol/g resin), which was washed with methanol (3×6 ml), and eluted with10% NH₃ in methanol, and concentrated to give the title compound. IR:1640, 1175, 1110, 805, 700, 620 cm⁻¹; LC-MS: (M+H)⁺ 446.3, t_(r) 5.62min.

Example 9N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-N′-phenylmethylcarbamidehydrochloride (26HCH16D)

To a solution of 1-benzyl-4-piperidone (1.74 g, 9.2 mmol) and4-methylbenzylamine (0.97 g, 8 mmol) in methanol (30 ml) was addedsodium borohydride (525 mg) in small portions over 30 min. The reactionmixture was stirred at room temperature. After 16 h, the mixture wasconcentrated. Water (30 ml) was added, and the mixture was extractedwith dichloromethane (2×20 ml). The combined organic layers were dried(Na₂SO₄), filtered, and concentrated to give4-((4-methylphenyl)methyl)amino-1-phenylmethylpiperidine. The crudeproduct was used without further purification.

4-((4-Methylphenyl)methyl)amino-1-phenylmethylpiperidine (800 mg, 2.7mmol) was dissolved in dry dichloromethane (30 ml). Benzylisocyanate(543 mg, 4.1 mmol) was added. The reaction mixture was stirred at roomtemperature. After 16 h, water (10 ml) was added followed by NaOH (6 N,2 ml). After additional 30 minutes of stirring the white crystals werefiltered off. The organic layer was isolated and dried (Na₂SO₄),filtered, and concentrated. Flash chromatography indichloromethane/methanol 10/1 leftN-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-N′-phenylmethylcarbamideYield: 820 mg, 71%; A sample was concentrated with HCl (4 M in dioxane)followed by recrystallization from dichloromethane/diethyl ether leavingthe title compound. ¹H-NMR (CDCl₃): δ 1.87 (br d, 2 H), 2.30 (s, 3 H),2.59 (dq, 2 H), 2.76 (br q, 2 H), 3.44 (br d, 2 H), 4.09 (d, 2 H), 4.30(d, 2 H), 4.40 (s, 2 H), 4.64-4.76 (m, 2 H), 6.98-7.64 (Aromaticprotons, 14 H); ¹³C-NMR (CDCl₃): δ 21.2, 26.7, 45.0, 46.0, 49.7, 52.2,61.0, 126.2, 127.26, 126.31, 128.2, 128.6, 129.6, 129.9, 130.4, 131.6,134.4, 137.6, 139.3, 158.5; ¹³C-NMR (CD₃OD, rotamers): δ 19.8, 26.4,27.8, 40.3, 44.3, 51.6, 51.9, 54.5, 60.5, 110.0, 112.1, 114.0, 114.2,117.5, 125.9, 126.2, 126.7, 126.8, 128.9, 129.1, 129.2, 129.4, 129.7,130.1, 131.2, 134.5, 137.4, 159.1, 173.8, 175.0; Mp. 109-112° C.;Elemental analysis: Found C, 70.06; H, 7.62; N, 8.60; calcd formonohydrate: C, 69.76; H, 7.53; N, 8.72.

Example 10N-((4-Methylphenyl)methyl)-N-(1-(1-phenylmethyl)piperidin-4-yl)-N′-phenylmethylcarbamideoxalate (34JJ59oxal)

N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-N′-phenylmethylcarbamidewas prepared as described in example 9 above. A sample was precipitatedas the oxalate and recrystallized from ethyl acetate to give the titlecompound. ¹³C-NMR (CDCl₃): δ 21.2, 27.0, 45.0, 45.9, 49.9, 52.1, 60.6,126.1, 127.3, 127.4, 128.5, 128.7, 129.6, 130.0, 130.4, 131.2, 134.3,137.7, 139.3, 158.4, 163.4; Mp. 180-182° C.; Elemental analysis: FoundC, 69.54; H, 6.73; N, 7.96; calcd for monooxalate: C, 69.61; H, 6.82; N,8.12.

Example 11N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-4-methoxyphenylacetamidehydrochloride (26HCH17)

To a solution of 1-benzyl-4-piperidone (1.74 g, 9.2 mmol) and4-methylbenzylamine (0.97 g, 8 mmol) in methanol (30 ml) was addedsodium borohydride (525 mg) in small portions over 30 min. The reactionmixture was stirred at room temperature. After 16 h, the mixture wasconcentrated. Water (30 ml) was added, and the mixture was extractedwith dichloromethane (2×20 ml). The combined organic layers were dried(Na₂SO₄), filtered, and concentrated to give4-((4-methylphenyl)methyl)amino-1-phenylmethylpiperidine. The crudeproduct was used without further purification.

To a solution of4-((4-Methylphenyl)methyl)amino-1-phenylmethylpiperidine (800 mg, 2.7mmol) in dry dichloromethane (30 ml) was added diisopropylethylamine(1.5 ml) followed by 4-methoxyphenylacetyl chloride (997 mg, 5.4 mmol).The reaction mixture was stirred at room temperature. After 16 h, thereaction mixture was concentrated, redissolved in diethyl ether, andextracted with HCl (0.6 N). The aqueous layer was isolated, treated withNaOH (1 N) until basic, and extracted with dichloromethane (20 ml). Theorganic layer was isolated and dried (Na₂SO₄), filtered, andconcentrated, and redissolved in diethyl ether. The hydrochloride wasformed by addition of HCl (4 M in dioxane), and recrystallized fromdiethyl ether to give the title compound. Yield: 600 mg, 50%; ¹H-NMR(CDCl₃): δ 1.75 (d, 2 H), 2.32 (s, 3 H), 2.50 (q, 2 H), 2.70 (q, 2 H),3.38 (d, 2 H), 3.54 (s, 2 H), 3.78 (s, 3 H), 4.06 (d, 2 H), 4.54 (s, 2H), 4.82 (m, 1 H), 6.78-7.60 (aromatic protons, 13 H); ¹³C-NMR (CDCl₃):δ 21.0, 26.0, 40.3, 46.3, 49.0, 51.8, 55.3, 60.8, 114.2, 125.6, 126.6,127.9, 129.4, 129.60, 129.62, 130.3, 131.4, 134.8, 137.1, 158.7, 172.9;Mp. 197-200° C.; Elemental analysis: Found C, 71.29; H, 7.25; N, 5.73;calcd for hydrate: C, 71.37; H, 7.43; N, 5.74.

Example 12N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-4-methoxyphenylacetamideoxalate (34JJ61oxal)

N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-4-methoxyphenylacetamidewas prepared as described in example 11 above. A sample was precipitatedas the oxalate and recrystallized from tetrahydrofuran to give the titlecompound. ¹³C-NMR (CDCl₃): δ 21.2,26.4,40.6, 52.0, 55.5, 114.4, 125.9,126.7, 128.4, 129.6, 129.8, 129.9, 130.4, 131.2, 134.6, 137.6, 158.9,163.3, 172.9; Mp. 171-173° C.; Elemental analysis: Found C, 69.56; H,6.74; N, 5.16; calcd for monooxalate: C, 69.48; H, 6.61; N, 5.40.

Example 13N-((4-Methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide(26HCH71B)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml)followed by NaCNBH₃ in methanol (0.3 M, 30 ml). The resulting solutionwas stirred at room temperature. After 20 h, water (5 ml) was added, andthe mixture was stirred for 1 h before it was concentrated. Flashchromatography in dichloromethane:methanol 10:1 gave tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4 g,98%. To a solution of tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate (862 mg, 2.83mmol) in dry dichloromethane (10 ml) was added diisopropylethylamine(1.1 ml, 6.5 mmol) followed by 4-methoxyphenylacetyl chloride (0.66 ml,4.3 mmol). The reaction mixture was stirred at room temperature. After48 h, water (5 ml) was added, and the mixture was stirred for additional2 h before extracted with NaOH (0.2 N, 2×15 ml), HCl (0.2 N, 2×15 ml),and water (15 ml). The organic layer was dried (Na₂SO₄) and concentratedto giveN-((4-methylphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide.The crude product was used without any further purification.N-((4-Methylphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamidewas dissolved in ether (2 ml) and HCl (3 ml, 4 M in dioxane) was added.The reaction mixture was stirred at room temperature. After 2 h, water(5 ml) was added, and the mixture was extracted with HCl (0.1 N, 3×30ml). The combined aqueous layers were treated with NaOH (0.2 N) untilbasic (pH>8). The aqueous layer was extracted with diethyl ether (2×20ml). The combined organic layers were dried (Na₂SO₄) and concentrated,before dissolved in methanol (2 ml). The solution was added on to acolumn carrying strongly acidic cation exchange resin (0.3 mmol/gresin), which was washed with methanol (3×6 ml), and eluted with 10% NH₃in methanol, and concentrated. Additional flash chromatography indichloromethane/methanol 1/1→methanol containing 2% NH3 gave the titlecompound. Yield: 466mg, 47%; ¹³C-NMR (CD₃OD, rotamers): δ 19.9, 27.8,29.7, 40.2, 40.3, 44.4, 44.45, 44.50, 52.4, 54.5, 55.5, 114.0, 114.1,126.0, 126.7, 126.9, 127.3, 128.7, 129.3, 129.6, 129.7, 135.1, 136.1,136.2, 137.1, 159.0, 159.1, 173.1, 173.7.

Example 14N-(1-(3,3-Dimethylbutyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide(26HCH79-5)

The product from example 13 above (20 mg, 0.06 mmol) was dissolved inabs. ethanol (2 ml). 3,3-Dimethylbutyraldehyde (0.143 ml, 1.1 mmol) wasadded followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin;Aldrich 32,864-2). The mixture was shaken at room temperature. After 48h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol)was added to the organic solution. After 24 h, the mixture wasconcentrated and redissolved in methanol (2 ml). The solution was addedon to a column carrying strongly acidic cation exchange resin (0.3mmol/g resin), which was washed with methanol (3×6 ml), and eluted with10% NH₃ in methanol, and concentrated to give the title compound. Yield:26 mg; ¹³C-NMR (CD₃OD, rotamers): δ 19.9, 27.4, 28.4, 28.8, 29.2, 29.3,38.3, 38.4, 40.2, 40.3, 44.3, 52.0, 52.3, 52.4, 53.9, 54.6, 54.9, 114.0,114.1, 126.0, 126.8, 127.0, 127.3, 128.8, 129.4, 129.8, 129.9, 135.0,136.1, 136.3, 137.1, 158.96, 159.05, 173.2, 173.8.

Example 15N-(1-(Cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide(26HCH79-6)

The product from example 13 above (20 mg, 0.06 mmol) was dissolved inabs. ethanol (2 ml). Cyclohexanecarboxaldehyde (0.138 ml, 1.1 mmol) wasadded followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin;Aldrich 32,864-2). The mixture was shaken at room temperature. After 48h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol)was added to the organic solution. After 24 h, the mixture wasconcentrated and redissolved in methanol (2 ml). The solution was addedon to a column carrying strongly acidic cation exchange resin (0.3mmol/g resin), which was washed with methanol (3×6 ml), and eluted with10% NH₃ in methanol, and concentrated to give the title compound. Yield:17 mg; HRMS (FAB⁺, NBA) (M+H)⁺ 449.3163, C₂₉H₄₁N₂O₂ requires 449.3168;LC-MS: (M+H)⁺ 449.2, t_(r) 7.92 min.

Example 16N-((4-Methylphenyl)methyl)-N-(1-(2-methylpropyl)piperidin-4-yl)-4-methoxyphenylacetamide(26HCH79-7)

The product from example 13 above (20 mg, 0.06 mmol) was dissolved inabs. ethanol (2 ml).). 2-Methylpropionaldehyde (0.104 ml, 1.1 mmol) wasadded followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin;Aldrich 32,864-2). The mixture was shaken at room temperature. After 48h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol)was added to the organic solution. After 24 h, the mixture wasconcentrated and redissolved in methanol (2 ml). The solution was addedon to a column carrying strongly acidic cation exchange resin (0.3mmol/g resin), which was washed with methanol (3×6 ml), and eluted with10% NH₃ in methanol, and concentrated to give the title compound. Yield:19 mg; HRMS (FAB⁺, NBA) (M+H)+409.2858, C₂₆H₃₇N₂O₂ requires 409.2855;LC-MS: (M+H)⁺ 409.2, t_(r) 5.97 min.

Example 17N-((4-Methylphenyl)methyl)-N-(1-((4-methylphenyl)methyl)piperidin-4-yl)-4-methoxyphenylacetamide(26HCH79-8)

The product from example 13 above (20 mg, 0.06 mmol) was dissolved inabs. ethanol (2 ml). 4-Methylbenzaldehyde (0.134 ml, 1.1 mmol) was addedfollowed by solid-supported borohydride (150 mg, 2.5 mmol/g resin;Aldrich 32,864-2). The mixture was shaken at room temperature. After 48h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol)was added to the organic solution. After 24 h, the mixture wasconcentrated and redissolved in methanol (2 ml). The solution was addedon to a column carrying strongly acidic cation exchange resin (0.3mmol/g resin), which was washed with methanol (3×6 ml), and eluted with10% NH₃ in methanol, and concentrated to give the title compound. Yield:22 mg; HRMS (FAB⁺, NBA) (M+H)⁺ 457.2853, C₃₀H₃₇N₂O₂ requires 457.2855;LC-MS: (M+H)⁺ 457.2, t_(r) 6.97 min.

Example 18N-(1-((4-Hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide(26HCH79-9)

The product from example 13 above (20 mg, 0.06 mmol) was dissolved inabs. ethanol (2 ml). 4-Hydroxybenzaldehyde (139 mg, 1.1 mmol) was addedfollowed by solid-supported borohydride (150 mg, 2.5 mmol/g resin;Aldrich 32,864-2). The mixture was shaken at room temperature. After 48h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol)was added to the organic solution. After 24 h, the mixture wasconcentrated and redissolved in methanol (2 ml). The solution was addedon to a column carrying strongly acidic cation exchange resin (0.3mmol/g resin), which was washed with methanol (3×6 ml), and eluted with10% NH₃ in methanol, and concentrated to give the title compound. Yield:19 mg; HRMS (FAB⁺, NBA) (M+H)⁺ 459.2655, C₂₉H₃₅N₂O₃ requires 459.2648;LC-MS: (M+H)⁺ 459.1, t_(r) 2.84 min.

Example 19N-(1-((2-Hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide(26HCH79-10)

The product from example 13 above (20 mg, 0.06 mmol) was dissolved inabs. ethanol (2 ml). 2-Hydroxybenzaldehyde (0.122 ml, 1.1 mmol) wasadded followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin;Aldrich 32,864-2). The mixture was shaken at room temperature. After 48h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol)was added to the organic solution. After 24 h, the mixture wasconcentrated and redissolved in methanol (2 ml). The solution was addedon to a column carrying strongly acidic cation exchange resin (0.3mmol/g resin), which was washed with methanol (3×6 ml), and eluted with10% NH₃ in methanol, and concentrated to give the title compound. Yield:16 mg; HRMS (FAB⁺, NBA) (M+H)⁺ 459.2633, C₂₉H₃₅N₂O₃ requires 459.2648;LC-MS: (M+H)⁺ 459.2, t_(r) 5.81 min.

Example 20N-(3-Phenylpropyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide(26HCH80-1)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-phenylpropylamine(0.143 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol(1 M, 1.34 ml) followed by NaCNBH₃ in methanol (0.3 M, 4.4 ml). Theresulting solution was stirred at room temperature. After 24 h, water (2ml) was added, and the mixture was stirred for 1 h, before it wasconcentrated. The resulting oil was redissolved in diethyl ether (20ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washedwith diethyl ether (10 ml) and treated with 0.2 N NaOH until basic(pH>8), before extracted with dichloromethane (20 ml). The organic layerwas dried (Na₂SO₄), filtered, and concentrated to give tert-butyl4-(3-phenylpropyl)amino-piperidine carboxylate. Yield: 110 mg. To asolution of tert-butyl 4-(3-phenylpropyl)amino-piperidine carboxylate(50 mg, 0.16 mmol) in dichloromethane (6 ml) was addeddiisopropylethylamine (0.070 ml, 0.4 mmol) followed by4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reactionmixture was stirred at room temperature. After 18 h, water (2 ml) wasadded. The mixture was stirred for another 2 h. The mixture wassequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml),and water (10 ml), dried (Na₂SO₄), filtered and concentrated to giveN-(3-phenylpropyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide.The crude product was used without any further purification.N-(3-Phenylpropyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamidewas dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) wasadded. The reaction mixture was stirred at room temperature. After 2.5h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). Themixture was extracted with water (2×15 ml), dried (Na₂SO₄), filtered togive a clear solution. The solution was added on to a column carryingstrongly acidic cation exchange resin (0.3 mmol/g resin), which waswashed with methanol (3×6 ml), and eluted with 10% NH₃ in methanol, andconcentrated to give the title compound. Yield: 61 mg; ¹³C-NMR (CD₃OD,rotamers): δ 27.8, 29.4, 30.8, 32.3, 32.7, 33.3, 40.2, 40.5, 42.0, 44.5,44.6, 44.9, 52.7, 54.56, 54.57, 54.9, 114.0, 114.1, 125.7, 126.1, 127.0,127.4, 128.2, 128.3, 128.5, 129.47, 129.55, 141.2, 141.8, 158.9, 159.0,172.5, 172.7.

Example 21N-(2-Phenylethyl)-N-(piperidin-4-yl)-4-methoxyphenylmethylacetamide(26HCH80-2)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-phenylethylamine(0.143 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol(1 M, 1.34 ml) followed by NaCNBH₃ in methanol (0.3 M, 4.4 ml). Theresulting solution was stirred at room temperature. After 24 h, water (2ml) was added, and the mixture was stirred for 1 h, before it wasconcentrated. The resulting oil was redissolved in diethyl ether (20ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washedwith diethyl ether (10 ml) and treated with 0.2 N NaOH until basic(pH>8), before extracted with dichloromethane (20 ml). The organic layerwas dried (Na₂SO₄), filtered, and concentrated to give tert-butyl4-(2-phenylethyl)amino-piperidine carboxylate. Yield: 221 mg. To asolution of tert-butyl 4-(2-phenylethyl)amino-piperidine carboxylate (50mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine(0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055ml, 0.35 mmol). The reaction mixture was stirred at room temperature.After 18 h, water (2 ml) was added. The mixture was stirred for another2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH(0.2 N, 2×15 ml), and water (10 ml), dried (Na₂SO₄), filtered andconcentrated to giveN-(2-phenylethyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide.The crude product was used without any further purification.N-(2-Phenylethyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamidewas dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) wasadded. The reaction mixture was stirred at room temperature. After 2.5h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). Themixture was extracted with water (2×15 ml), dried (Na₂SO₄), filtered togive a clear solution. The solution was added on to a column carryingstrongly acidic cation exchange resin (0.3 mmol/g resin), which waswashed with methanol (3×6 ml), and eluted with 10% NH₃ in methanol, andconcentrated to give the title compound. Yield: 52 mg; ¹³C-NMR (CD₃OD,rotamers): δ 27.1, 28.5, 34.9, 36.6, 40.2, 40.4, 44.1, 44.2, 44.4, 53.3,54.2, 54.6, 114.0, 114.1, 126.2, 126.6, 127.2, 127.4, 128.3, 128.6,128.79, 128.82, 129.7, 138.5, 139.5, 158.96, 159.0, 172.7, 173.1

Example 22N-((2-Methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylmethylacetamide(26HCH80-4)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-methoxybenzylamine(0.130 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol(1 M, 1.34 ml) followed by NaCNBH₃ in methanol (0.3 M, 4.4 ml). Theresulting solution was stirred at room temperature. After 24 h, water (2ml) was added, and the mixture was stirred for 1 h, before it wasconcentrated. The resulting oil was redissolved in diethyl ether (20ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washedwith diethyl ether (10 ml) and treated with 0.2 N NaOH until basic(pH>8), before extracted with dichloromethane (20 ml). The organic layerwas dried (Na₂SO₄), filtered, and concentrated to give tert-butyl4-((2-methoxyphenyl)methyl)amino-piperidine carboxylate. Yield: 211 mg.To a solution of tert-butyl 4-((2-methoxyphenyl)methyl)amino-piperidinedichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol).The reaction mixture was stirred at room temperature. After 18 h, water(2 ml) was added. The mixture was stirred for another 2 h. The mixturewas sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15ml), and water (10 ml), dried (Na₂SO₄), filtered and concentrated togiveN-((2-methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide.The crude product was used without any further purification.N-((2-Methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamidewas dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) wasadded. The reaction mixture was stirred at room temperature. After 2.5h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). Themixture was extracted with water (2×15 ml), dried (Na₂SO₄), filtered togive a clear solution. The solution was added on to a column carryingstrongly acidic cation exchange resin (0.3 mmol/g resin), which waswashed with methanol (3×6 ml), and eluted with 10% NH₃ in methanol, andconcentrated to give the title compound. Yield: 40 mg; ¹³C-NMR (CD₃OD,rotamers): δ 26.1, 27.4, 40.0, 40.1, 43.5, 43.9, 51.5, 53.4, 54.5,54.58, 54.63, 54.78, 54.83, 110.1, 110.5, 113.76, 113.78, 113.84, 114.0,114.1, 120.1, 120.5, 125.4, 126.0, 126.5, 126.7, 127.1, 127.3, 127.7,128.8, 129.8, 130.0, 130.08, 130.14, 156.5, 157.0, 159.0, 159.1, 173.2,173.8.

Example 23N-((2-Chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide(26HCH80-5)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-chlorobenzylamine(0.121 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol(1 M, 1.34 ml) followed by NaCNBH₃ in methanol (0.3 M, 4.4 ml). Theresulting solution was stirred at room temperature. After 24 h, water (2ml) was added, and the mixture was stirred for 1 h before it wasconcentrated. The resulting oil was redissolved in diethyl ether (20ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washedwith diethyl ether (10 ml) and treated with 0.2 N NaOH until basic(pH>8), before extracted with dichloromethane (20 ml). The organic layerwas dried (Na₂SO₄), filtered, and concentrated to give tert-butyl4-((2-chlorophenyl)methyl)amino-piperidine carboxylate. Yield: 137 mg.To a solution of tert-butyl 4-((2-chlorophenyl)methyl)amino-piperidinecarboxylate (50 mg, 0.15 mmol) in dichloromethane (6 ml) was addeddiisopropylethylamine (0.070 ml, 0.4 mmol) followed by4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reactionmixture was stirred at room temperature. After 18 h, water (2 ml) wasadded. The mixture was stirred for another 2 h. The mixture wassequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml),and water (10 ml), dried (Na₂SO₄), filtered and concentrated to giveN-((2-chlorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide.The crude product was used without any further purification.N-((2-Chlorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamidewas dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) wasadded. The reaction mixture was stirred at room temperature. After 2.5h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). Themixture was extracted with water (2×15 ml), dried (Na₂SO₄), filtered togive a clear solution. The solution was added on to a column carryingstrongly acidic cation exchange resin (0.3 mmol/g resin), which waswashed with methanol (3×6 ml), and eluted with 10% NH₃ in methanol, andconcentrated to give the title compound. Yield: 45 mg; ¹³C-NMR (CD₃OD,rotamers): δ 25.8, 26.9, 40.0, 40.1, 42.9, 43.4, 43.7, 46.0, 51.1, 53.0,54.6, 113.77, 113.84, 114.0, 114.1, 126.6, 126.8, 127.08, 127.13, 127.3,127.4, 128.1, 129.0, 129.2, 129.8, 130.0, 130.2, 131.9, 132.2, 135.0,135.3, 159.1, 173.4, 173.8.

Example 24N-((3,4-Di-methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide(26HCH80-6)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (400 mg, 2 mmol) in methanol (1 ml) and3,4-di-methoxybenzylamine (0.151 ml, 1 mmol) in methanol (1 ml) wasadded acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH₃ inmethanol (0.3 M, 4.4 ml). The resulting solution was stirred at roomtemperature. After 24 h, water (2 ml) was added, and the mixture wasstirred for 1 h, before it was concentrated. The resulting oil wasredissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15ml). The aqueous layer was washed with diethyl ether (10 ml) and treatedwith 0.2 N NaOH until basic (pH>8), before extracted withdichloromethane (20 ml). The organic layer was dried (Na₂SO₄), filtered,and concentrated to give tert-butyl4-((3,4-di-methoxyphenyl)methyl)amino-piperidine carboxylate. Yield: 162mg. To a solution of tert-butyl4-((3,4-di-methoxyphenyl)methyl)amino-piperidine carboxylate (50 mg,0.14 mmol) in dichloromethane (6 ml) was added diisopropylethylamine(0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055ml, 0.35 mmol). The reaction mixture was stirred at room temperature.After 18 h, water (2 ml) was added. The mixture was stirred for another2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH(0.2 N, 2×15 ml), and water (10 ml), dried (Na₂SO₄), filtered andconcentrated to giveN-((3,4-di-methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide.The crude product was used without any further purification.N-((3,4-Di-methoxyphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamidewas dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) wasadded. The reaction mixture was stirred at room temperature. After 2.5h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). Themixture was extracted with water (2×15 ml), dried (Na₂SO₄), filtered togive a clear solution. The solution was added on to a column carryingstrongly acidic cation exchange resin (0.3 mmol/g resin), which waswashed with methanol (3×6 ml), and eluted with 10% NH₃ in methanol, andconcentrated to give the title compound. Yield: 54 mg; ¹³C-NMR (CD₃OD,rotamers): δ 25.9, 27.3, 40.0, 40.1, 43.5, 43.8, 44.1, 51.4, 53.5, 54.6,55.4, 110.2, 111.0, 111.9, 112.2, 114.0, 114.2, 118.6, 119.4, 127.1,127.4, 129.9, 130.0, 130.5, 132.1, 148.2, 148.7, 149.2, 149.7, 158.98,159.05, 173.3, 173.6.

Example 25N-((4-Fluorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide(26HCH80-7)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (400 mg, 2 mmol) in methanol (1 ml) and 4-fluorobenzylamine(0.114 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol(1 M, 1.34 ml) followed by NaCNBH₃ in methanol (0.3 M, 4.4 ml). Theresulting solution was stirred at room temperature. After 24 h, water (2ml) was added, and the mixture was stirred for 1 h, before it wasconcentrated. The resulting oil was redissolved in diethyl ether (20ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washedwith diethyl ether (10 ml) and treated with 0.2 N NaOH until basic(pH>8), before extracted with dichloromethane (20 ml). The organic layerwas dried (Na₂SO₄), filtered, and concentrated to give tert-butyl4-((4-fluorophenyl)methyl)amino-piperidine carboxylate. Yield: 130 mg.To a solution of tert-butyl 4-((4-fluorophenyl)methyl)amino-piperidinecarboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was addeddiisopropylethylamine (0.070 ml, 0.4 mmol) followed by4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reactionmixture was stirred at room temperature. After 18 h, water (2 ml) wasadded. The mixture was stirred for another 2 h. The mixture wassequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml),and water (10 ml), dried (Na₂SO₄), filtered and concentrated to giveN-((4-fluorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide.The crude product was used without any further purification.N-((4-Fluorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamidewas dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) wasadded. The reaction mixture was stirred at room temperature. After 2.5h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). Themixture was extracted with water (2×15 ml), dried (Na₂SO₄), filtered togive a clear solution. The solution was added on to a column carryingstrongly acidic cation exchange resin (0.3 mmol/g resin), which waswashed with methanol (3×6 ml), and eluted with 10% NH₃ in methanol, andconcentrated to give the title compound. Yield: 45 mg; ¹³C-NMR (CD₃OD,rotamers): δ 26.1, 27.5, 40.1, 43.6, 43.8, 44.0, 51.6, 53.6, 54.6,113.77, 113.84, 114.0, 114.1, 114.7, 114.9, 115.3, 115.6, 126.8, 127.2,128.1, 128.6, 128.7, 129.8, 130.0, 130.1, 130.6, 131.0, 133.8, 159.1,173.3, 173.6.

Example 26N-((2,4-Di-chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide(26HCH80-8)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (400 mg, 2 mmol) in methanol (1 ml) and2,4-di-chlorobenzylamine (0.135 ml, 1 mmol) in methanol (1 ml) was addedacetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH₃ in methanol(0.3 M, 4.4 ml). The resulting solution was stirred at room temperature.After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h,before it was concentrated. The resulting oil was redissolved in diethylether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layerwas washed with diethyl ether (10 ml) and treated with 0.2 N NaOH untilbasic (pH>8), before extracted with dichloromethane (20 ml). The organiclayer was dried (Na₂SO₄), filtered, and concentrated to give tert-butyl4-((2,4-di-chlorophenyl)methyl)amino-piperidine carboxylate. Yield: 97mg. To a solution of tert-butyl4-((2,4-di-chlorophenyl)methyl)amino-piperidine carboxylate (50 mg, 0.14mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35mmol). The reaction mixture was stirred at room temperature. After 18 h,water (2 ml) was added. The mixture was stirred for another 2 h. Themixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N,2×15 ml), and water (10 ml), dried (Na₂SO₄), filtered and concentratedto giveN-((2,4-di-chlorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide.The crude product was used without any further purification.N-((2,4-Di-chlorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamidewas dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) wasadded. The reaction mixture was stirred at room temperature. After 2.5h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). Themixture was extracted with water (2×15 ml), dried (Na₂SO₄), filtered togive a clear solution. The solution was added on to a column carryingstrongly acidic cation exchange resin (0.3 mmol/g resin), which waswashed with methanol (3×6 ml), and eluted with 10% NH₃ in methanol, andconcentrated to give the title compound. Yield: 39 mg; ¹³C-NMR (CD₃OD,rotamers): δ 25.7, 26.8, 40.0, 42.6, 43.3, 43.7, 51.2, 53.0, 54.5, 54.6,113.8, 113.8, 114.0, 114.1, 127.0, 128.4, 128.8, 129.8, 130.0, 130.1,131.0, 132.7, 132.9, 134.5, 159.1, 173.4, 173.6.

Example 27N-((3-Methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide(26HCH80-9)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-methylbenzylamine(0.125 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol(1 M, 1.34 ml) followed by NaCNBH₃ in methanol (0.3 M, 4.4 ml). Theresulting solution was stirred at room temperature. After 24 h, water (2ml) was added, and the mixture was stirred for 1 h, before it wasconcentrated. The resulting oil was redissolved in diethyl ether (20ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washedwith diethyl ether (10 ml) and treated with 0.2 N NaOH until basic(pH>8), before extracted with dichloromethane (20 ml). The organic layerwas dried (Na₂SO₄), filtered, and concentrated to give tert-butyl4-((3-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 136 mg.To a solution of tert-butyl 4-((3-methylphenyl)methyl)amino-piperidinecarboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was addeddiisopropylethylamine (0.070 ml, 0.4 mmol) followed by4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reactionmixture was stirred at room temperature. After 18 h, water (2 ml) wasadded. The mixture was stirred for another 2 h. The mixture wassequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml),and water (10 ml), dried (Na₂SO₄), filtered and concentrated to giveN-((3-methylphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide.The crude product was used without any further purification.N-((3-Methylphenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamidewas dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) wasadded. The reaction mixture was stirred at room temperature. After 2.5h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). Themixture was extracted with water (2×15 ml), dried (Na₂SO₄), filtered togive a clear solution. The solution was added on to a column carryingstrongly acidic cation exchange resin (0.3 mmol/g resin), which waswashed with methanol (3×6 ml), and eluted with 10% NH₃ in methanol, andconcentrated to give the title compound. Yield: 48 mg; ¹³C-NMR (CD₃OD,rotamers): δ 20.4, 26.8, 28.3, 40.2, 43.9, 44.1, 44.5, 51.8, 54.2,54.57, 54.61, 114.0, 114.1, 123.2, 123.7, 126.7, 127.0, 127.1, 127.3,128.0, 128.1, 128.7, 129.8, 129.9, 137.9, 138.6, 138.9, 159.0, 159.1,173.1, 173.7.

Example 28N-((3-Bromophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide(26HCH80-10)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-bromobenzylaminehydrobromide (222 mg, 1 mmol) in methanol (1 ml) was added acetic acidin methanol (1 M, 1.34 ml) followed by NaCNBH₃ in methanol (0.3 M, 4.4ml). The resulting solution was stirred at room temperature. After 24 h,water (2 ml) was added, and the mixture was stirred for 1 h, before itwas concentrated. The resulting oil was redissolved in diethyl ether (20ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washedwith diethyl ether (10 ml) and treated with 0.2 N NaOH until basic(pH>8), before extracted with dichloromethane (20 ml). The organic layerwas dried (Na₂SO₄), filtered, and concentrated to give tert-butyl4-((3-bromophenyl)methyl)amino-piperidine carboxylate. Yield: 142 mg. Toa solution of tert-butyl 4-((3-bromophenyl)methyl)amino-piperidinecarboxylate (50 mg, 0.14 mmol) in dichloromethane (6 ml) was addeddiisopropylethylamine (0.070 ml, 0.4 mmol) followed by4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reactionmixture was stirred at room temperature. After 18 h, water (2 ml) wasadded. The mixture was stirred for another 2 h. The mixture wassequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml),and water (10 ml), dried (Na₂SO₄), filtered and concentrated to giveN-((3-bromophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide.The crude product was used without any further purification.N-((3-Bromophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamidewas dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) wasadded. The reaction mixture was stirred at room temperature. After 2.5h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). Themixture was extracted with water (2×15 ml), dried (Na₂SO₄), filtered togive a clear solution. The solution was added on to a column carryingstrongly acidic cation exchange resin (0.3 mmol/g resin), which waswashed with methanol (3×6 ml), and eluted with 10% NH₃ in methanol, andconcentrated to give the title compound. Yield: 49 mg; ¹³C-NMR (CD₃OD,rotamers): δ 26.6, 28.2, 40.2, 43.9, 44.0, 51.8, 54.1, 54.6, 113.76,113.84, 114.1, 114.2, 122.2, 125.0, 125.5, 126.7, 127.1, 129.2, 129.5,129.7, 129.8, 129.9, 130.0, 130.5, 130.6, 140.8, 141.8, 159.1, 173.3,173.7.

Example 29N-(1-(Phenylmethyl)piperidin-4-yl)-N-(3-phenyl-2-propen-1-yl)-4-methoxyphenylacetamide(26HCH76B)

To a solution of 4-amino-N-benzylpiperidine (200 mg, 1.05 mmol) inmethanol (2 ml) was added trans-cinnamaldehyde (211 mg, 1.6 mmol),followed by Acetic acid in methanol (1 M, 1.4 ml) andsodiumcyanoborohydride in methanol (0.3 M, 4.4 ml). The reaction mixturewas stirred at room temperature. After 48 h, water (2 ml) was added. Themixture was stirred for another 2 h before concentrated and redissolvedin diethyl ether (20 ml). The organic layer was extracted with HCl (0.1N, 2×10 ml). The combined aqueous layers were treated with NaOH (0.2 N)until basic (pH>8). The mixture was extracted with dichloromethane (2×10ml). The combined organic layers were dried (Na₂SO₄) and concentrated.The crude product, which was used without any further purification, wasdissolved in dichloromethane (5 ml). Diisopropylethylamine (284 mg, 2.1eq.) was added, followed by 4-methoxyphenylacetyl chloride (387 mg, 2.0eq). The reaction mixture was stirred at room temperature. After 18 h,water (2 ml) was added. After additional 2 h dichloromethane (10 ml) wasadded. The mixture was extracted with NaOH (0.2 N, 3×15 ml), and water(15 ml). The organic layer was dried (Na₂SO₄) and concentrated. Thecrude product was redissolved in methanol (2 ml) and added on to acolumn carrying strongly acidic cation exchange resin (0.3 mmol/gresin), which was washed with methanol (3×6 ml), and eluted with 10% NH₃in methanol, and concentrated to give the title compound. ¹³C-NMR(CDCl₃): δ 28.5, 38.1, 46.6, 47.4, 50.9, 54.7, 62.9, 113.7, 125.5,126.4, 126.6, 127.4, 127.9, 128.5, 128.6, 129.6, 130.0, 135.2, 135.3,138.0, 158.2, 173.2.

Example 30N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-phenylacetamide(26HCH78-1)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml)followed by NaCNBH₃ in methanol (0.3 M, 30 ml). The resulting solutionwas stirred at room temperature. After 20 h, water (5 ml) was added, andthe mixture was stirred for 1 h, before it was concentrated. Flashchromatography in dichloromethane:methanol 10:1 gave tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4 g,98%. To a solution of tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol)in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml,2.4 eq.) followed by phenylacetyl chloride (81 mg, 0.53 mmol). Thereaction mixture was stirred at room temperature. After 20 h, water (1ml) was added. The mixture was stirred for another 2 h, before diethylether (20 ml) was added. The mixture was sequentially extracted with HCl(0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and H₂O (10 ml), dried(Na₂SO₄), filtered and concentrated. The crude material was dissolved indiethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reactionmixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) wasadded followed by dichloromethane (10 ml). The mixture was extractedwith water (2×10 ml), dried (Na₂SO₄), and filtered to give a clearsolution. The solution was added on to a column carrying strongly acidiccation exchange resin (0.3 mmol/g resin), which was washed with methanol(3×6 ml), and eluted with 10% NH₃ in methanol, and concentrated to givethe title compound. Yield: 38 mg; ¹³C-NMR (CD₃OD, rotamers): δ 19.9,26.9, 28.4, 41.0, 41.1, 44.0, 44.1, 44.4, 51.9, 54.4, 126.1, 126.7,126.8, 126.9, 128.5, 128.7, 128.78, 128.81, 128.9, 129.4, 129.5, 134.9,135.2, 135.6, 136.0, 136.3, 137.2, 172.8, 173.3.

Example 31N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-3-phenylpropionamide(26HCH78-2)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml)followed by NaCNBH₃ in methanol (0.3 M, 30 ml). The resulting solutionwas stirred at room temperature. After 20 h, water (5 ml) was added, andthe mixture was stirred for 1 h, before it was concentrated. Flashchromatography in dichloromethane:methanol 10:1 gave tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4 g,98%. To a solution of tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol)in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml,2.4 eq.) followed by 3-phenylpropionyl chloride (0.078 ml, 0.53 mmol).The reaction mixture was stirred at room temperature. After 20 h, water(1 ml) was added. The mixture was stirred for another 2 h, beforediethyl ether (20 ml) was added. The mixture was sequentially extractedwith HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and H₂O (10 ml), dried(Na₂SO₄), filtered and concentrated. The crude material was dissolved indiethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reactionmixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) wasadded followed by dichloromethane (10 ml). The mixture was extractedwith water (2×10 ml), dried (Na₂SO₄), and filtered to give a clearsolution. The solution was added on to a column carrying strongly acidiccation exchange resin (0.3 mmol/g resin), which was washed with methanol(3×6 ml), and eluted with 10% NH₃ in methanol, and concentrated to givethe title compound. Yield: 43 mg; ¹³C-NMR (CD₃OD, rotamers): δ 19.9,27.4, 29.0, 31.4, 31.7, 34.7, 35.7, 44.2, 44.3, 51.6, 54.2, 125.9,126.07, 126.15, 126.8, 128.3, 128.4, 128.7, 128.8, 129.3, 135.1, 136.1,136.2, 137.0, 141.1, 141.2, 173.9, 174.4.

Example 32N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-(phenylthio)acetamide(26HCH78-3)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml)followed by NaCNBH₃ in methanol (0.3 M, 30 ml). The resulting solutionwas stirred at room temperature. After 20 h, water (5 ml) was added, andthe mixture was stirred for 1 h, before it was concentrated. Flashchromatography in dichloromethane:methanol 10:1 gave tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4 g,98%. To a solution of tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol)in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml,2.4 eq.) followed by (phenylthio)acetyl chloride (0.078 ml, 0.53 mmol).The reaction mixture was stirred at room temperature. After 20 h, water(1 ml) was added. The mixture was stirred for another 2 h, beforediethyl ether (20 ml) was added. The mixture was sequentially extractedwith HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and H₂O (10 ml), dried(Na₂SO₄), filtered and concentrated. The crude material was dissolved indiethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reactionmixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) wasadded followed by dichloromethane (10 ml). The mixture was extractedwith water (2×10 ml), dried (Na₂SO₄), and filtered to give a clearsolution. The solution was added on to a column carrying strongly acidiccation exchange resin (0.3 mmol/g resin), which was washed with methanol(3×6 ml), and eluted with 10% NH₃ in methanol, and concentrated to givethe title compound. Yield: 18 mg; HRMS (FAB⁺, NBA) (M+H)⁺ 355.1841,C₂₁H₂₇N₂OS requires 355.1844; LC-MS: (M+H)⁺ 355.1, t_(r) 2.62 min.

Example 33N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-phenoxyacetamide(26HCH784)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml)followed by NaCNBH₃ in methanol (0.3 M, 30 ml). The resulting solutionwas stirred at room temperature. After 20 h, water (5 ml) was added, andthe mixture was stirred for 1 h, before it was concentrated. Flashchromatography in dichloromethane:methanol 10:1 gave tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4 g,98%. To a solution of tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26mmol)in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml,2.4 eq.) followed by phenoxyacetyl chloride (0.073 ml, 0.53 mmol). Thereaction mixture was stirred at room temperature. After 20 h, water (1ml) was added. The mixture was stirred for another 2 h, before diethylether (20 ml) was added. The mixture was sequentially extracted with HCl(0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and H₂O (10 ml), dried(Na₂SO₄), filtered and concentrated. The crude material was dissolved indiethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reactionmixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) wasadded followed by dichloromethane (10 ml). The mixture was extractedwith water (2×10 ml), dried (Na₂SO₄), and filtered to give a clearsolution. The solution was added on to a column carrying strongly acidiccation exchange resin (0.3 mmol/g resin), which was washed with methanol(3×6 ml), and eluted with 10% NH₃ in methanol, and concentrated to givethe title compound. Yield: 24 mg; ¹³C-NMR (CD₃OD, rotamers): δ 19.9,25.8, 27.4, 43.5, 43.7, 44.4, 51.9, 52.3, 66.9, 114.7, 114.8, 116.7,117.0, 121.4, 123.6, 126.3, 126.8, 128.4, 128.9, 129.3, 129.5, 129.6,131.0, 134.4, 136.1, 137.4, 158.3, 169.8, 170.1.

Example 34N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-(4-chlorophenoxy)acetamide(26HCH78-5)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml)followed by NaCNBH₃ in methanol (0.3 M, 30 ml). The resulting solutionwas stirred at room temperature. After 20 h, water (5 ml) was added, andthe mixture was stirred for 1 h, before it was concentrated. Flashchromatography in dichloromethane:methanol 10:1 gave tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4 g,98%. To a solution of tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol)in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml,2.4 eq.) followed by 4-chlorophenoxyacetyl chloride (0.082 ml, 0.53mmol). The reaction mixture was stirred at room temperature. After 20 h,water (1 ml) was added. The mixture was stirred for another 2 h, beforediethyl ether (20 ml) was added. The mixture was sequentially extractedwith HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and H₂O (10 ml), dried(Na₂SO₄), filtered and concentrated. The crude material was dissolved indiethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reactionmixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) wasadded followed by dichloromethane (10 ml). The mixture was extractedwith water (2×10 ml), dried (Na₂SO₄), and filtered to give a clearsolution. The solution was added on to a column carrying strongly acidiccation exchange resin (0.3 mmol/g resin), which was washed with methanol(3×6 ml), and eluted with 10% NH₃ in methanol, and concentrated to givethe title compound. Yield: 21 mg; ¹³C-NMR (CD₃OD, rotamers): δ 19.9,26.2, 27.8, 43.6, 43.9, 44.4, 52.2, 52.5, 67.0, 116.2, 116.4, 126.2,126.3, 126.8, 128.6, 128.9, 129.1, 129.3, 129.5, 131.0, 134.4, 135.6,136.4, 137.5, 157.1, 169.4, 169.7.

Example 35N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-3-methoxyphenylacetamide(26HCH78-6)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine-(970 mg, 8.0mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml)followed by NaCNBH₃ in methanol (0.3 M, 30 ml). The resulting solutionwas stirred at room temperature. After 20 h, water (5 ml) was added, andthe mixture was stirred for 1 h, before it was concentrated. Flashchromatography in dichloromethane:methanol 10:1 gave tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4 g,98%. To a solution of tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol)in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml,2.4 eq.) followed by 3-methoxyphenylacetyl chloride (97 mg, 0.53 mmol).The reaction mixture was stirred at room temperature. After 20 h, water(1 ml) was added. The mixture was stirred for another 2 h, beforediethyl ether (20 ml) was added. The mixture was sequentially extractedwith HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and H₂O (10 ml), dried(Na₂SO₄), filtered and concentrated. The crude material was dissolved indiethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reactionmixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) wasadded followed by dichloromethane (10 ml). The mixture was extractedwith water (2×10 ml), dried (Na₂SO₄), and filtered to give a clearsolution. The solution was added on to a column carrying strongly acidiccation exchange resin (0.3 mmol/g resin), which was washed with methanol(3×6 ml), and eluted with 10% NH₃ in methanol, and concentrated to givethe title compound. Yield: 26 mg; ¹³C-NMR (CD₃OD, rotamers): δ 19.9,26.3, 27.7, 41.0, 43.7, 43.9, 44.4, 51.5, 53.8, 54.5, 54.6, 112.2,112.6, 114.3, 114.5, 121.0, 121.2, 126.1, 126.8, 128.8, 129.4, 129.5,129.8, 134.8, 136.0, 136.3, 136.5, 136.9, 137.2, 160.2, 160.3, 172.8,173.2.

Example 36N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-4-fluorophenylacetamide(26HCH78-7)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml)followed by NaCNBH₃ in methanol (0.3 M, 30 ml). The resulting solutionwas stirred at room temperature. After 20 h, water (5 ml) was added, andthe mixture was stirred for 1 h, before it was concentrated. Flashchromatography in dichloromethane:methanol 10:1 gave tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4 g,98%. To a solution of tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol)in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml,2.4 eq.) followed by 4-fluorophenylacetyl chloride (0.072 ml, 0.53mmol). The reaction mixture was stirred at room temperature. After 20 h,water (1 ml) was added. The mixture was stirred for another 2 h, beforediethyl ether (20 ml) was added. The mixture was sequentially extractedwith HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and H₂O (10 ml), dried(Na₂SO₄), filtered and concentrated. The crude material was dissolved indiethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reactionmixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) wasadded followed by dichloromethane (10 ml). The mixture was extractedwith water (2×10 ml), dried (Na₂SO₄), and filtered to give a clearsolution. The solution was added on to a column carrying strongly acidiccation exchange resin (0.3 mmol/g resin), which was washed with methanol(3×6 ml), and eluted with 10% NH₃ in methanol, and concentrated to givethe title compound. Yield: 26 mg; ¹³C-NMR (CD₃OD, rotamers): δ 19.9,26.1, 27.4, 39.7, 39.9, 43.5, 43.8, 44.4, 51.3, 53.4, 114.9, 115.1,115.3, 126.1, 126.7, 128.5, 128.8, 129.4, 130.7, 130.8, 130.9, 131.0,131.2, 131.6, 134.8, 136.0, 136.3, 137.2, 160.9, 163.3, 172.7, 173.2.

Example 37N-((4-Methylphenyl)methyl)-N-(1-piperidin-4-yl)-2,5-di-methoxyphenylacetamide(26HCH78-8)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml)followed by NaCNBH₃ in methanol (0.3 M, 30 ml). The resulting solutionwas stirred at room temperature. After 20 h, water (5 ml) was added, andthe mixture was stirred for 1 h, before it was concentrated. Flashchromatography in dichloromethane:methanol 10:1 gave tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4 g,98%. To a solution of tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol)in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml,2.4 eq.) followed by 2,5-di-methoxyphenylacetyl chloride (0.092 ml, 0.53mmol). The reaction mixture was stirred at room temperature. After 20 h,water (1 ml) was added. The mixture was stirred for another 2 h, beforediethyl ether (20 ml) was added. The mixture was sequentially extractedwith HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and H₂O (10 ml), dried(Na₂SO₄), filtered and concentrated. The crude material was dissolved indiethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reactionmixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) wasadded followed by dichloromethane (10 ml). The mixture was extractedwith water (2×10 ml), dried (Na₂SO₄), and filtered to give a clearsolution. The solution was added on to a column carrying strongly acidiccation exchange resin (0.3 mmol/g resin), which was washed with methanol(3×6 ml), and eluted with 10% NH₃ in methanol, and concentrated to givethe title compound. 36 mg; ¹³C-NMR (CD₃OD, rotamers): δ 20.0, 26.5,28.2, 35.1, 35.7, 44.0, 44.4, 51.6, 53.8, 54.99, 55.03, 55.2, 55.5,111.4, 111.7, 112.4, 112.9, 116.6, 116.9, 124.98, 125.02, 126.1, 126.7,128.8, 129.3, 135.0, 136.1, 136.3, 137.0, 151.3, 151.7, 153.9, 154.0,173.1, 173.5.

Example 38 N-((4-Methylphenyl)methyl)-N-(1-piperidin4-yl)-4-chlorophenylacetamide (26HCH78-9)

To a solution of commercially available tert-butyl 4-oxo-1-piperidinecarboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml)followed by NaCNBH₃ in methanol (0.3 M, 30 ml). The resulting solutionwas stirred at room temperature. After 20 h, water (5 ml) was added, andthe mixture was stirred for 1 h, before it was concentrated. Flashchromatography in dichloromethane:methanol 10:1 gave tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4 g,98%. To a solution of tert-butyl4-(4-methylphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol)in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml,2.4 eq.) followed by 4-chlorophenylacetyl chloride (99 mg, 0.53 mmol).The reaction mixture was stirred at room temperature. After 20 h, water(1 ml) was added. The mixture was stirred for another 2 h, beforediethyl ether (20 ml) was added. The mixture was sequentially extractedwith HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and H₂O (10 ml), dried(Na₂SO₄), filtered and concentrated. The crude material was dissolved indiethyl ether (2 ml) and HCl (4 M in dioxane, 1 ml). The reactionmixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) wasadded followed by dichloromethane (10 ml). The mixture was extractedwith water (2×10 ml), dried (Na₂SO₄), and filtered to give a clearsolution. The solution was added on to a column carrying strongly acidiccation exchange resin (0.3 mmol/g resin), which was washed with methanol(3×6 ml), and eluted with 10% NH₃ in methanol, and concentrated to givethe title compound. Yield: 22 mg; ¹³C-NMR (CD₃OD, rotamers): δ 19.9,26.3, 27.7, 39.9, 40.0, 43.6, 43.9, 44.4, 51.5, 53.6, 126.1, 126.7,128.2, 128.4, 128.6, 128.9, 129.4, 129.6, 130.7, 130.9, 131.2, 131.6,132.5, 132.7, 133.9, 134.1, 134.4, 134.8, 135.9, 136.3, 137.2, 172.4,172.9.

Example 39N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-N′-phenylmethylcarbamide(26HCH50)

To a solution of 3-amino-1-phenylmethylpyrrolidine (353 mg, 2 mmol) and4-methylbenzaldehyde (361 mg, 3 mmol) in methanol (20 ml) was addedacetic acid in methanol (2 M, 6.7 ml) followed by NaCNBH₃ in methanol(0.3 M, 3 ml). The mixture was stirred at room temperature. After 24 h,water (5 ml) was added. The mixture was stirred for another hour beforeconcentrated. Flash chromatography in dichloromethane/methanol 10/1 gaveN-((4-methylphenyl)methyl)amino-1-phenylmethylpyrrolidine.

N-((4-Methylphenyl)methyl)amino-1-phenylmethylpyrrolidine (35 mg, 0.125mmol) was dissolved in dichloromethane (1.5 ml), and benzylisocyanate(0.09 ml, 0.3 mmol) was added. The reaction mixture was stirred at roomtemperature. After 48 h, the crude reaction mixture was added on to acolumn carrying strongly acidic cation exchange resin, which was washedwith methanol (3×6 ml), and eluted with 10% NH₃ in methanol, andconcentrated to give the title compound. Yield: 48 mg, 92%; ¹³C-NMR(CD₃OD): δ 20.0, 29.7, 44.2, 51.3, 53.4, 56.4, 57.8, 58.7, 126.8, 127.1,127.3, 127.6, 128.3, 128.4, 128.9, 129.1, 135.9, 136.8, 140.3, 158.5.

Example 40N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-4-methoxyphenylacetamide(26HCH52)

To a solution of 3-amino-1-phenylmethylpyrrolidine (353 mg, 2 mmol) and4-methylbenzaldehyde (361 mg, 3 mmol) in methanol (20 ml) was addedacetic acid in methanol (2 M, 6.7 ml) followed by NaCNBH₃ in methanol(0.3 M, 3 ml). The mixture was stirred at room temperature. After 24 h,water (5 ml) was added. The mixture was stirred for another hour beforeconcentrated. Flash chromatography in dichloromethane/methanol 10/1 gaveN-((4-methylphenyl)methyl)amino-1-phenylmethylpyrrolidine.

To a solution ofN-((4-Methylphenyl)methyl)amino-1-phenylmethylpyrrolidine (35 mg, 0.125mmol), diisopropylethylamine (0.14 ml) in dichloromethane (1.5 ml) wasadded 4-methoxyphenylacetyl chloride (0.1 ml, 0.5 mmol). The reactionmixture was stirred at room temperature. After 48 h, the crude reactionmixture was concentrated and redissolved in methanol. The solution wasadded on to a column carrying strongly acidic cation exchange resin,which was washed with methanol (3×6 ml), and eluted with 10% NH₃ inmethanol, and concentrated. Flash chromatography indichloromethane/methanol 10/1 gave the title compound. Yield: 20 mg,38%; ¹³C-NMR (CD₃OD): δ 21.3, 30.2, 40.8, 47.8, 53.6, 53.9, 55.5, 57.5,60.2, 114.4, 125.7, 127.0, 127.1, 127.3, 127.4, 128.4, 128.5, 128.7,128.9, 129.2, 129.8, 130.0, 135.9, 137.0, 158.6.

Example 41N-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-4-methoxyphenylthioacetamide(RO)

A mixture ofN-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-(4-methoxyphenylmethyl)acetamide(20 mg, 0.045 mmol) and Lawesson's reagent (25 mg, 0.062 mmol), wastaken in a glass vial and mixed thoroughly with magnetic stirbars. Theglass vial was then irradiated in a microwave oven (900 W, WhirlpoolM401) for 8 min. Upon completion of the reaction, the yellow-coloredmaterial was transferred to an ion-exchange column with the aid ofmethanol (2 ml). The ion-exchange column was subsequently washed withCH₂Cl₂ (2 ml) and methanol (2 ml) and the product was thereafter elutedfrom the ion-exchange column (10% NH₃ in methanol, 2 ml) to giveN-((4-Methylphenyl)methyl)-N-(1-(phenylmethyl)piperidin-4-yl)-4-methoxyphenylmethylthioacetamide (20 mg, 97%) as a white solid; LC-MS: (M+H)⁺ 459, t_(r)9.60 min; TLC (CH₂Cl₂/methanol 20:1) R_(f)=0.38.

Example 42 Receptor Selection and Amplification (R-SAT) Assays

The functional receptor assay, Receptor Selection and AmplificationTechnology (R-SAT), was used (with minor modifications from thatpreviously described U.S. Pat. No. 5,707,798) to screen compounds forefficacy at the 5-HT2A receptor. Briefly, NIH3T3 cells were grown in 96well tissue culture plates to 70-80% confluence. Cells were transfectedfor 12-16 hours with plasmid DNAs using superfect (Qiagen Inc.) as permanufacture's protocols. R-SAT's were generally performed with 50ng/well of receptor and 20 ng/well of Beta-galactosidase plasmid DNA.All receptor and G-protein constructs used were in the pSI mammalianexpression vector (Promega Inc) as described in U.S. Pat. No. 5,707,798.The 5HT2A receptor gene was amplified by nested PCR from brain cDNAusing the oligodeoxynucleotides based on the published sequence (seeSaltzman et. al. Biochem. Biophys. Res. Comm. 181:1469-78 (1991)).Large-scale transfections, cells were transfected for 12-16 hours, thentrypsinized and frozen in DMSO. Frozen cells were later thawed, platedat 10,000-40,000 cells per well of a 96 well plate that contained drug.With both methods, cells were then grown in a humidified atmosphere with5% ambient CO2 for five days. Media was then removed from the plates andmarker gene activity was measured by the addition of thebeta-galactosidase substrate ONPG (in PBS with 5% NP-40). The resultingcolorimetric reaction was measured in a spectrophotometric plate reader(Titertek Inc.) at 420 nM. All data were analyzed using the computerprogram XLFit (IDBSm). Efficacy is the percent maximal repressioncompared to repression by a control compound (ritanserin in the case of5HT2A). pIC50 is the negative of the log(IC50), where IC50 is thecalculated concentration in Molar that produces 50% maximal repression.The results obtained for six compounds of the invention are presented inthe following table. TABLE 1 Efficacy of Compounds at the 5-HT2AReceptor Efficacy Efficacy pIC50 pIC50 Compound (average) (stdev)(average) (stdev) 26HCH52 98 5.0 7.31 0.16 26HCH66-03 76 13.3 7.42 0.0126HCH66-05 109 3.0 7.55 0.15 26HCH80-2 89 4.6 7.78 0.17 26HCH80-7 87 3.77.70 0.26 26HCH80-10 91 4.9 7.21 0.05

Example 43 In Vitro Efficacy of 26HCH17 as an Inverse Agonist at the5-HT2A Receptor

The graph shown in FIG. 1 represents the data obtained from a doseresponse analysis of 26HCH17 and ritanserin as 5-HT2A receptor inverseagonists. Briefly, the 5-HT2A receptor, and the alpha subunit of theguanine nucleotide binding protein Gq were transiently transfected intoNIH3T3 cells and assayed using the functional receptor assay, ReceptorSelection and Amplification Technology (R-SAT) essentially as disclosedin U.S. Pat. No. 5,707,798. Each compound was screened at seven seriallydiluted concentrations in triplicate. Data were analyzed using leastsquares fit analysis with GraphPad Prism (San Diego, Calif.), and arereported normalized to percent response.

Example 44 Selectivity Profile of Inverse Agonist 26HCH16D

R-SAT assays (as described in Example 42) were carried out with cellstransfected with receptors (listed below) to determine the receptorselectivity profile for compound 26HCH16D. 5HT2A inverse agonist data(IC50 nM; % efficacy) were derived from detailed dose response curves (7points in triplicate). All other data (initial concentration at which atleast 30% efficacy observed; actual efficacy figure) derived from the 4dose profiling protocol in which compounds were tested at 4 doses induplicate. nr=activity less than 30% at all doses tested (3, 30, 300,3000 nM), therefore EC50/IC50 greater than 300 nM). The results arepresented in the following table. TABLE 2 Profile of 5-HT2A InverseAgonist 26HCH16D Receptor Efficacy 5HT2A (human) Agonist nr InverseAgonist   0.9 nM; 79% 5HT2B (human) Agonist nr Antagonist 3000 nM; 60%5HT2C (human) Agonist nr Inverse Agonist 3000 nM; 79% 5HT1A (human)Agonist nr Antagonist nr 5HT1A (rat) Antagonist nr 5HT1E (human) Agonistnr D2 (human) Agonist nr Antagonist 3000 nM; 73% H1 (human) Agonist nrAntagonist 3000 nM; 30% alpha1a/D (rat) Agonist nr Antagonist nralpha1b/B (hamster) Agonist nr Antagonist nr alpha1c/A (human) Agonistnr Antagonist 3000 nM; 46% alpha2A (human) Agonist nr Antagonist nralpha2B (human) Agonist nr Antagonist nr alpha2C (human) Agonist nrAntagonist nr m1 (human) Agonist nr Antagonist nr

As indicated above, 26HCH16D is a highly selective 5-HT2A inverseagonist

General LC-MS Procedure for Working Examples ELH01-46, MBT01-14 andAKUO1-38.

In the following examples, HPLC/MS analyses were performed using eitherof two general methods (Method A or Method B). The t_(r) values reportedbelow were obtained using one of these procedures, as indicated in thespecific examples.

The methods were as follows:

Method A: Agilent HP1100 HPLC/MSD.

G1312A Binary pump, G1313A Autosampler, G1316A Column compartment,G1315A Diode array detector (190-450 nm), 1946A MSD, electrosprayionization.

Chromatography:

8 mM ammoniumacetate in water/acetonitrile.

Gradient start at 70% org. up to 100% org. over 12 min, down to 70% org.over 0.5 min, held for 3.5 min. Total runtime 16 min. Flowrate 1 ml/min

Column, Phenomenex Luna C1 8(2) 3um 75×4.6 mm.

MS Parameters:

Drying gas, 10 l/min. Nebulizer pressure, 40 psig. Gas temp, 350 C.VCap, 4000.

Method B: Waters/Micromass HPLC/MS

600 LC-pump, 2700 Sample manager, 2487 Dual absorbance detector (channelA-205 nm, channel B-235 nm), Micromass ZMD-mass-spectrometer,electrospray ionization.

Chromatography:

0.15% TFA in water/acetonitrile.

Gradient start at 30% org. up to 100% org. over 10 min, held for 3 min.down to 30% org. over 0.5 min, held for 4.5 min. Total run time 18 min.Flowrate, 1 ml/min.

Column, Symmetry C18, 5 μm, 4.6×50 mm. or

10 mM ammoniumacetate in water/acetonitrile.

Gradient start at 30% org. for 2.5 min, up to 100% org. over 10 min,held for 9 min, down to 30% org. over 0.5 min, held for 5 min. Total runtime 27 min. Flowrate, 1 ml/min.

Column: Phenomenex Synergi C12, 4 μm, 4.6×50 mm.

MS Parameters:

Desolvation gas, 404 l/H. Capillary, 5.3kV. Cone, 36V. Extractor, 3V.Source block temp, 130 C. Desolvation temp, 250 C.

Example 452-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(piperidin-4-yl)acetamide(50ELH87) Reaction Step 1: N-trifluoroacetyl-4-piperidone (50ELH84)

4-Piperidone hydrochloride monohydrate (4.0 g, 26 mmol, 1.0 eq) wasdissolved in 130 ml of dichloromethane. After addition of triethylamine(8.66 g, 3.3 eq) the reaction mixture was stirred for 10 min. Themixture was cooled on an ice-bath (0° C.). Trifluoroacetic anhydride(12.0 g, 2.2 eq) was added dropwise under stirring. After 2 hours thereaction was quenched by addition of distilled water. The aqueous phasewas extracted twice with dichloromethane. The combined organic layerswere collected and dried with sodium sulfate. Concentration affordedN-trifluoroacetyl-4-piperidone.

Reaction Step 2: 4-(4-Methylbenzylamino)-1-(trifluoroacetyl)piperidin(50ELH85)

Methanol (150 ml) was added to an Erlenmeyer flask and acetic acid wasadded under stirring until pH 5. 4-Methylbenzylamine (3.14 g, 25.9 mmol)and N-trifluoroacetyl-4-piperidone(from reaction step 1) (5.065 g, 25.9mmol) were added to a 250 ml round-bottomed flask and dissolved in themethanol/acetic acid (150 ml) solution previously made. The reactionmixture was stirred for 5 min and NaCNBH₃ (2.46 g, 38.9 mmol) was addedslowly under stirring. After 20 hours the reaction was concentrated andtransferred to a separatory funnel containing dichloromethane anddistilled water. The aqueous phase was made basic by addition of Na₂CO₃.The aqueous phase was extracted twice with dichloromethane. The combinedorganic layers were collected and dried with Na₂SO₄. Concentrationafforded, 4-(4-methylbenzylamine)-1-(trifluoroacetyl)piperidine. UV/MS60/53 (M⁺ 301), t_(r) (A, MS) 3.267.

Reaction Step 3:2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-trifluoroacetylpiperidin-4-yl)acetamide(50ELH86)

The product from reaction step 2 (7.8 g, 25.9 mmol) was dissolved in 100ml of dichloromethane and stirred while 4-methoxyphenylacetyl chloride(4.8 g, 25.9 mmol) was added. After 4 hours, heptane was added whereuponthe product precipitated as the hydrochloride salt. The solvent wasremoved by evaporation. The crude material was purified by flashchromatography EtOAc/Heptane (1:2) Yield (overall: Reaction steps 1+2+3)3.912 g (34%), UV/MS 91/58 (M⁺ 449), t_(r) (A, MS) 4.319. ¹H-NMR (400MHz, CDCl₃) δ 6.80-7.15 (Ar, 4H), 4.64 (brt, 1H), 4.4 (s, 2H), 3.95 (d,2H), 3.72 (s, 3H), 3.50 (s, 2H), 3.09 (t, 2H), 2.7(t, 2H), 2.32 (s, 3H),1.75 (brt, 2H). ¹³C-NMR 172.5; 158.8; 137.4; 134.9; 129.9; 129.9; 129.8;127.1; 125.8; 114.3; 55.4; 52.2; 47.3; 45.3; 43.4.40.6; 30.1; 29.2;21.2.

Reaction Step 4:2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(piperidin-4-yl)acetamide(50ELH87)

The product from reaction step 3 (3.9 g, 8.7 mmol) was dissolved inmethanol (12 ml). In a 250 ml round bottom flask a saturated solution ofpotassium carbonate in methanol was prepared. To this solution, the2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(N-trifluoroacetpiperidin-4-yl)acetamidesolution was added under stirring. After 4 hours, the solution wasconcentrated and the remaining solid taken upin base anddichloromethane. The combined organic layers were dried with sodiumsulfate and concentrated. UV/MS 91/72 (M⁺ 353), t_(r) (A, MS) 2.210.

The corresponding hydrochloride salt was also prepared, by dissolvingthe free base in dichloromethane (1 ml) and HCl (1 eq. 2 M HCl in ether)was added with stirring. The salt was precipitated by addition of thedichloromethane solution into heptane. Concentration on the rotaryevaporator returned the product is white crystals.

Example 462-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH27) Reaction Step 1: 4-(4-Methylbenzylamino)-1-methylpiperidine(50ELH25)

Methanol (50 ml) was added to an Erlenmeyer flask and acetic acid wasadded under stirring until pH 5. Methylbenzylamine (1.0 g, 8.8 mmol) and1-Methyl-4-piperidone (1.1 g, 8.8 mmol) were added to a 100 mlround-bottomed flask and dissolved in the methanol/acetic acid (40 ml)solution previously made. The reaction mixture was stirred for 5 min andNaCNBH₃ (0.83 g, 13.2 mmol) was added slowly under stirring. After 20hours the reaction was concentrated and transferred to a separatoryfunnel containing dichloromethane and distilled water. The aqueous phasewas made basic by addition of Na₂CO₃. The aqueous phase was extractedtwice with dichloromethane. The combined organic layers were collectedand dried with Na₂SO₄. Concentration afforded the title compound. Yield(crude): 98%. UV/MS 89/88 (M⁺ 353), t_(r) (A, MS) 3.982.

Reaction Step 2:2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH27)

The product from reaction step 1-(1.9 g, 8.7 mmol) was dissolved in 40ml of dichloromethane and stirred while 4-methoxyphenylacetylchloride(1.606 g, 8.7 mmol) was added. After 4 hours, heptane was addedwhereupon the product precipitated as the hydrochloride salt. Thesolvent was removed by evaporation. The crude material was purified byflash chromatography first eluting with 10% MeOH in CH₂Cl₂ andthereafter eluting with 0-20% MeOH in CH₂Cl₂ and 5% NEt₃. Yield(overall: Reaction steps 1+2): 77%. UV/MS: 100/100 (M⁺ 367), t_(r) (A,MS) 4.359, R_(f) 0.15 (2% MeOH in CH₂Cl₂). ¹H-NMR (400 MHz, CDCl₃) δ12.6 (s, 1H), 7.16 (d, J=7.0 Hz, 2H), 7.10 (d, J=7.0 Hz, 2H), 7.04 (d,J=8.0 Hz, 2H), 6.82 (d, J=8.0 Hz, 2H), 4.87 (tt, J=1.0, 4.0 Hz, 1H),4.53 ppm (s, 2H), 3.78 (s, 3H), 3.55 (s, 2H), 3.42 (brd, J=11.0 Hz, 2H),2.80 (brq, J=11.0 Hz, 2H), 2.7 (d, J=4.0 Hz, 3H), 2.42 (dq, J=13.0, 3.0Hz, 2H), 2.34 (s, 3H), 1.78 (brd, J=13.0 Hz, 2H). ¹³C-NMR 173.1; 158.9;137.4; 134.8; 129.9; 126.7; 125.8; 114.4; 76.9; 55.5; 54.6; 48.8; 43.7;40.5; 26.4; 21.2

Example 472-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclohexylmethylpiperidin-4-yl)acetamide(42ELH45)

50ELH87 (the hydrochloride salt) (0.5 g, 1.29 mmol, 1.0 eq) wasdissolved in ethanol (100 ml). Cyclohexanecarboxaldehyde (2.5 g, 20 eq.)was added followed by addition of sodium borohydride (0.084 g, 2.0 eq.).The reaction was stirred for 36 h and acetic acid (3 ml) was added. Thereaction was stirred for additionally 2 h and extracted with sodiumhydrogen carbonate (3 times) and dichloromethane. The organic layerswere dried with sodium sulfate and concentrated. The product waspurified by flash chromatography (1-10% MeOH in CH₂Cl₂). The resultingproduct was dissolved in ether (20 ml) and MeOH (added dropwise untildissolved) and HCl (1 eq. 2 M HCl in ether) was added under stirring.The hydrochloride salt of2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclohexylmethylpiperidin-4-yl)acetamideprecipitated and the white crystals were filtered. Yield 80 mg (16%),UV/MS 100/100 (M⁺ 449), r_(t) (A, MS) 7.105, mp 133-135° C., R_(f) 0.25(2% MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, CDCl₃) δ 11.9 (brs, 1H), 7.12 (q,4H), 7.02 (d, 2H), 6.80 (d, 2H), 4.87 (m, 1H), 4.58 (s, 2H), 3.77 (s,3H), 3.55 (s, 2H), 3.48 (m, 2H), 2.70 (m, 4H), 2.31 (s, 3H), 1.91 (d,2H), 1.75 (m, 3H), 1.64 (d, 1H), 1.22 (d, 2H), 1.13 (tt, 2H), 1.02 (brq,2H). ¹³C-NMR 173.1; 158.8; 137.2; 135.1; 129.9; 129.8; 126.8; 125.8;114.4; 64.1; 55.5; 53.4; 49.2; 46.5; 40.4; 33.9; 25.9; 25.8; 25.7; 21.2.

Example 482-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperidin-4-yl)acetamide(42ELH80)

50ELH87 (0.25 g, 0.71 mmol, 1.0 eq) was dissolved in acetonitrile (15ml) and ethyl bromide (0.232 g, 3.0 eq.) was added under stirring. After2 min Hünigs base (0.084 g, 10.0 eq.) was added. After 36 hours, thesolution was extracted with sodium hydrogen carbonate solution anddichloromethane (3 times). The organic layers were dried with sodiumsulfate and concentratedyielding a yellow oil. The product was purifiedby flash chromatography (2% MeOH in CH₂Cl₂). The resulting product wasdissolved in dichloromethane (1 ml) and HCl (1 eq. 2 M HCl in ether) wasadded under stirring. The salt was precipitated by addition of thedichloromethane solution into heptane. Concentrationon the rotaryevaporator gave the product as white crystals. Yield 170 mg (63%), UV/MS98/95 (M⁺ 381), mp 153-155° C., r_(t) (A, MS) 3.033, R_(f) 0.35 (3%MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, CDCl₃) δ 12.2 (s, 1H), 7.15 (d, 2H), 7.12(d, 2H), 7.08 (d, 2H), 6.82 (d, 2H), 4.89 (m, 1H), 4.58 (s, 2H), 3.79(s, 3H), 3.58 (s, 2H), 3.50 (d, 2H), 2.90 (m, 1H), 2.7 (brq, 2H), 2.45(m, 2H), 2.34 (s, 3H), 1.80 (d, 2H), 1.44 (t, 3H). ¹³C-NMR 173.1; 158.9;137.3; 134.9; 129.9; 125.8; 114.4; 55.5; 52.3; 52.0; 49.2; 46.5; 40.5;26.2; 21.2; 9.5.

Example 492-(4-Methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-ethylpiperidin-4-yl)acetamide(42ELH85)

This compound was prepared similarly to 50ELH27

Reaction-Step 1: (42ELH84)

Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.),4-chlorobenzylamine (0.626 g, 1.0 eq.), sodium cyanoborohydride (0.279g, 1.5 eq.).

Reaction-Step 2: (42ELH85)

Starting materials: 42ELH84, 4-methoxyphenylacetylchloride (0.774 g, 1.0eq.).

The procedure was analogous to 50ELH27, but the product was purified byion-exchange chromatography followed by HPLC. The hydrochloride salt wasmade by dissolving the free base in dichloromethane (1 ml) and HCl (1eq. 2 M HCl in ether) was added under stirring. The salt wasprecipitated by addition of the dichloromethane solution into heptanefollowed by concentration on the rotary evaporator.

Product: White crystals. UV/MS 98/97 (M⁺ 387), r_(t) (A, MS) 2.953.¹H-NMR (400 MHz, CDCl₃) δ 12.6 (s, 1H), 7.35 (d, 2H), 7.18 (d, 2H), 7.65(d, 2H), 6.82 (d, 2H), 4.89 (m, 1H), 4.55 (s, 2H), 3.80 (s, 3H), 3.55(s, 2H), 3.45 (brs, 2H), 2.80 (brs, 2H), 2.72 (s, 3H), 2.25 (brs, 3H),1.80 (brs, 2H). ¹³C-NMR 173.0; 158.9; 136.5; 133.6; 129.8; 129.4; 127.3;126.3; 114.5; 55.5; 54.6; 48.7; 46.3; 43.7; 40.5; 26.3.

502-(4-Methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-isopropylpiperidin-4-yl)acetamide(42ELH79)

Procedure as 42ELH80

Starting materials: 50ELH87 (0.25 g, 0.71 mmol, 1.0 eq.),isopropylbromide (0.262 g, 3.0 eq.).

Product: Yield 130 mg (46%), UV/MS 100/100 (M⁺ 395), r_(t) (A, MS)3.360. ¹H-NMR (400 MHz, CDCl₃) δ 12.0 (s, 1H), 7.15 (d, 2H), 7.10 (d,2H), 7.05 (d, 2H), 6.82 (d, 2H), 4.87 (m, 1H), 4.60 (s, 2H), 3.79 (s,3H), 3.57 (s, 2H), 3.38 (brd, 3H), 2.79 (q, 2H), 2.63 (q, 2H), 2.34 (s,3H), 1.80 (d, 2H), 1.39 (d, 6H). ¹³C-NMR 173.1; 158.9; 137.3; 135.1;129.8; 126.8; 125.8; 114.4; 57.9; 49.4; 48.2; 46.5; 40.5; 25.9; 21.2;16.9.

Example 512-(4-Methoxyphenyl)-N-(4-chlorobenzyl)-N-(piperidin-4-yl)acetamide(42ELH89) (As Starting Material in Other Reactions, Used Unpurified)

Procedure as 50ELH27.

Reaction Step 1: N-Trifluoroacetyl-4-piperidone (42ELH86)

Starting materials: 4-Piperidone hydrochloride monohydrate (2.0 g, 13mmol, 1.0 eq), trifluoroacetic anhydride (6.0, 2.2 eq.). TLC showed fullconversion.

Product: R_(f) 0.9 (10% MeOH/CH₂Cl₂).

Reaction Step 2: 4-(4-Chlorobenzylamino)-1-(trifluoroacetyl)piperidin(42ELH87)

Starting materials: 42ELH86 (2.5 g, 12.8 mmol, 1.0 eq.),4-Chlorobenzylamine (1.8 g, 1.0 eq.)

Reaction Step 3:2-(4-Methoxyphenyl)-N-(4-chlorobenzyl)-N-(1-trifluoroacetylpiperidin-4-yl)acetamide(42ELH88)

Starting materials: 42ELH87 (4.0 g, 12.5 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (2.31 g, 1.0 eq.)

Reaction Step 4:2-(4-Methoxyphenyl)-N-(4-chlorobenzyl)-N-(piperidin-4-yl)acetamide(42ELH89)

Product: Yield: 2 g (57%), UV/MS 80/82 (M⁺ 373), R_(f) 0.2 (50%EtOAc/Heptane).

Example 522-(4-Methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-cyclopentylpiperidin-4-yl)acetamide(42ELH91)

Procedure as 42ELH80, but the product was purified by HPLC. The acidiceluent was made basic with sodium carbonate and extracted withdichloromethane (3 times). The combined organic layers were collectedand dried with sodium sulfate and concentrated. The remaining productwas dissolved in I ml of dichloromethane and HCl (1 eq. 2 M HCl inether) was added under stirring. This solution was added drop-wise to alarge excess of n-heptane to make the hydrochloride precipitate. Thesolvent was evaporated off to form white crystals of2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-cyclopentylpiperidin-4-yl)acetamide,hydrochloride.

Starting materials: 42ELH89 (0.25 g, 0.67 mmol, 1.0 eq.),cyclopentylbromide (0.3, 3.0 eq.)

Product: Yield: 211.2 mg (76%). Purification by ion-exchange: UV/MS90/98. Purification by HPLC UV/MS 100/100 (M⁺ 441), R_(f) 0.2 (3%MeOH/CH₂Cl₂), r_(t) (A, MS) 4.067. ¹H-NMR (400 MHz, CDCl₃) δ 12.2 (brs,1H), 7.32 (d, 2H), 7.17 (d, 2H), 7.04 (d, 2H), 6.82 (d, 2H), 4.90 (brt,1H), 4.58 (s, 2H), 3.79 (s, 3H), 3.58 (brd, 2H), 3.54 (s, 2H), 3.14(brq, 2H), 2.58 (brq, 2H), 2.04 (m, 4H), 1.89 (m, 4H), 1.75 (brd, 2H).¹³C-NMR 173.0; 158.9; 133.5; 129.8; 129.3; 127.3; 126.4; 114.5; 68.4;55.5; 51.9; 49.1; 46.2; 40.5; 28.5; 26.0; 23.8.

Example 532-(4-Methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-isopropylpiperidin-4-yl)acetamide(42ELH90)

42ELH89 (0.25 g, 0.67 mmol, 1.0 eq) was transferred to a 4 ml vial anddissolved in acetonitrile (2 ml). Isopropyl bromide (0.25 g, 3.0 eq.)was added along with Hünigs base (0.87 g, 10.0 eq.). The vial was sealedand shaken for 4 days at 60° C. The reaction mixture was transferred toa separatory funnel with distilled water and CH₂Cl₂. The aqueous phasewas made basic with sodium hydrogen carbonate and extracted withdichloromethane (3 times). The organic layers were collected and driedwith sodium sulfate and concentrated, this resulted in a yellow oil. Theproduct was purified by flash chromatography (3% MeOH in CH₂Cl₂). Theresulting product was dissolved in dichloromethane (1 ml) and HCl (1 eq.2 M HCl in ether) was added under stirring. The salt precipitated byaddition of the dichloromethane solution into heptane. Concentration onthe rotary evaporator returned the product as white crystals. Yield101.2 mg (63%), UV/MS 94/96 (M⁺ 415), R_(f) 0.25 (3% MeOH/CH₂Cl₂).

¹H-NMR (400 MHz, CDCl₃) δ 12.05 (brs, 1H), 7.36 (d, 2H), 7.18 (d, 2H),7.04 (d, 2H), 6.82 (d, 2H), 4.88(m, 1H), 4.60 (s, 2H), 3.79 (s, 3H),3.55 (d, 2H), 3.36 (d, 3H), 2.80 (brq, 2H), 2.65 (brq, 2H), 1.76 (brd,2H), 1.39 (d, 6H). ¹³C-NMR 173.0; 159.0; 137.0; 136.0; 129.7; 129.3;127.4; 126.4; 114.5; 57.9; 55.5; 49.2; 48.2; 46.2; 40.5; 25.8; 16.9.

Example 542-(Phenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH14b)

Procedure as for 50ELH27. Purification was done by HPLC. Thehydrochloride salt was made by dissolving the free-base indichloromethane (1 ml) and HCl (1 eq. 2 M HCl in ether) was added understirring. The salt was precipitated by addition of the dichloromethanesolution into heptanefollowed by concentration.

Reaction-Step 1: 4-(4-Triflouromethylbenzylamino)-1-methylpiperidin(50ELH2)

Starting materials: 1-Methyl piperidone (1.13 g, 10.0 mmol, 1.0 eq.),4-trifluoromethylbenzylamine (1.75 g, 1.0 eq.).

Product: UV/MS 80/92 (M⁺ 273).

Reaction-Step 2:2-(Phenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH14b)

Starting materials: 50ELH2 (0.12 g, 0.44 mmol, 1.0 eq.),phenylacetylchloride (0.068 g, 1.0 eq.).

Product: UV/MS 100/97 (M⁺ 390), r_(t) (A, MS) 3.797, R_(f) 0.3 (5%MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, CDCl₃, rotamers 54/46) δ 7.52 (d, 2H),7.42 (d, 2H), 7.12-7.30 (m, 4H,), 4.63 and 3.74 (2m, 1H), 4.38 (brs,2H), 3.80 and 3.50 (2s, 3H), 3.31 and 2.78 (2d, 2H), 2.33 and 2.18 (2s,2H), 2.24 and 1.65-1.90 (t and m, 4H), 1.60 and 1.22 (2d, 2H), 1.¹³C-NMR 172.3; 171.8; 143.9; 135.1; 134.8; 129.1; 129.0; 128.9; 128.7;127.4; 127.3; 127.2; 126.3; 126.1; 126.0; 56.0; 55.2; 54.9; 30 50.9;46.8; 45.2; 44.9; 42.2; 41.7; 30.6; 28.4.

Example 552-(4-Fluorophenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH14c)

Procedure as 50ELH14B.

Reaction-Step 2:2-(4-Fluorophenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH14c)

Starting materials: 50ELH2 (0.12 g, 0.44 mmol, 1.0 eq.),4-fluorophenylacetylchloride (0.076 g, 1.0 eq.).

Product: Yield 69.7 mg (36%), UV/MS 100/98 (M⁺ 409), r_(t) (A, MS)3.839, R_(f) 0.3 (5% MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, DMSO, rotamers65/35) δ 10.80 and 10.60 (2s, 1H), 7.71 and 7.62 (2d, 2H), 7.47 and 7.38(2d, 2H), 7.00-7.36 (t and m, 4H), 4.70 and 4.50 (2s, 2H), 4.30 (m, 1H),3.93 and 3.56 (2s, 2H), 3.34 (s, 2H), 3.00 (brq, 2H), 2.64 (s, 3H), 2.08(m, 2H), 1.68 and 1.58 (2d, 2H). ¹³C-NMR 176.8; 176.4; 167.6; 165.3;150.0; 149.0; 136.6; 132.5; 131.0; 130.5; 120.6; 120.5; 120.5; 120.4;58.1; 58.0; 57.0; 54.5; 52.0; 49.3; 47.6; 45.0; 32.4; 31.4.

Example 562-(4-Methoxyphenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH14d)

Procedure as 50ELH14B.

Reaction-Step 2:2-(4-Methoxyphenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH14d)

Starting materials: 50ELH2 (0.15 g, 0.55 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.1 g, 1.0 eq.).

Product: Yield 57.5 mg (29%), UV/MS 99/100 (M⁺ 421), r_(t) (B, MS) 6.30,R_(f) 0.25 (3% MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, CDCl₃) δ 12.4 (brs, 1H),7.55 (d, 2H), 7.28 (d, 2H), 6.96 (d, 2H), 4.84 (brt, 1H), 4.59 (s, 2H),3.72 (s, 3H), 3.46 (s, 2H), 3.38 (d, 2H), 2.78 (q, 2H), 2.64 (s, 3H),2.38 (q, 2H), 1.70 (d, 2H). ¹³C-NMR 173.0; 159.0; 142.3; 130.0; 129.8;126.3; 126.2; 114.7; 114.5; 55.5; 54.4; 48.7; 46.5; 43.6; 40.6; 26.3.

Example 572-(4-Trifluoromethylphenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH14a)

Procedure as 50ELH14B.

Reaction-Step 2:2-(4-Trifluoromethylphenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH 14a)

Starting materials: 50ELH2 (0.12 g, 0.44 mmol, 1.0 eq.),4-trifluoromethylphenylacetylchloride (0.1 g, 1.0 eq.).

Product: Yield 92.6 mg (42%), UV/MS 89/93 (M⁺ 458), r_(t) (A, MS) 4.211,R_(f) 0.3 (5% MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, CDCl₃) δ 12.7 (brs, 1H),7.56 (d, 2H), 7.48 (d, 2H), 7.17 (d, 2H), 4.86 (m, 1H), 4.63 (s, 2H),3.58 (s, 3H), 3.40 (d, 2H), 2.75 (q, 2H), 2.65 (d, 3H), 2.46 (dq, 2H),1.73 (brs, 2H). ¹³C-NMR 171.8; 141.9; 138.4; 129.4; 127.9; 126.3; 126.3;126.2; 125.9; 125.8; 54.4; 48.8; 46.6; 43.6; 40.9; 26.2.

Example 582-(4-Fluorophenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH6) Procedure as 50ELH14B Reaction-Step 1:4-(4-Fluorobenzylamino)-1-methylpiperidine (50ELH4)

Starting materials: 1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.),4-fluorobenzylamine (1.25 g, 1.0 eq.).

Product: Yield 2.154 g (97%), UV/MS 79/89 (M⁺ 223).

Reaction-Step 2:2-(4-Fluorophenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH14a)

Starting materials: 50ELH4 (0.12 g, 0.54 mmol, 1.0 eq.),4-fluorophenylacetylchloride (0.096 g, 1.0 eq.).

Product: Yield 57 mg (29%), UV/MS 100/100 (M⁺ 359), r_(t) (A, MS) 3.763,R_(f) 0.25 (3% MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, CDCl₃) δ 12.6 (brs, 1H),7.2 (dd, 2H), 7.06 (m, 4H), 6.98 (t, 2H), 4.88 (tt, 1H), 4.58 (s, 4H),3.45 (d, 2H), 2.81 (q, 2H), 2.72 (d, 3H), 2.48 (brq, 2H), 1.78 (brs,2H). ¹³C-NMR 172.5; 163.4; 160.8; 133.4; 130.6; 130.2; 127.5; 127.4;116.3; 116.1; 115.9; 115.7; 54.5; 48.8; 46.2; 43.6; 40.3; 26.3.

Example 592-(4-Methoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH8)

Procedure as 50ELH14B

Reaction-step 2:

Starting materials: 50ELH4 (0.12 g, 0.54 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.1 g, 1.0 eq.).

Product: Yield 54 g (26%), UV/MS 100/100 (M⁺ 371), r_(t) (A, MS) 3.257,R_(f) 0.25 (3% MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, CDCl₃) δ 12.2 (brs, 1H),7.12 (m, 2H), 6.97 (m, 4H), 6.75 (d, 2H), 4.80 (brt, 1H), 4.49 (s, 2H),3.71 (s, 3H), 3.47 (s, 2H), 3.37 (d, 2H), 2.8 (q, 2H), 2.64 (s, 3H),2.35 (q, 2H), 1.69 (d, 2H). ¹³C-NMR 173.0; 163.5; 161.1; 158.9; 133.7;133.6; 129.8; 127.6; 127.5; 126.5; 116.2; 116.0; 114.6; 114.5; 55.5;54.4; 48.8; 46.2; 43.6; 40.5; 26.4.

Example 602-(phenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH10)

Procedure as 50ELH14B.

Reaction-Step 2:2-(Phenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH10)

Starting materials: 50ELH4 (0.13 g, 0.59 mmol, 1.0 eq.),phenylacetylchloride (0.091 g, 1.0 eq.).

Product: UV/MS 100/94 (M⁺ 341), r_(t) (A, MS) 3.127, R_(f) 0.25 (3%MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, DMSO, rotamers 54/56) δ 12.38 (brs, 1H),7.35-7.00 (m, 9H), 4.55 and 4.40 (2s, 2H), 4.50 and 4.25 (brt, 1H), 3.91and 3.56 (2s, 2H), 3.30 (Hidden under water signal)(2H), 2.98 (d, 2H),2.64 (s, 3H), 2.09 (brt, 2H), 1.66 and 1.45 (2brd, 2H). ¹³C-NMR 171.9;171.6; 162.8; 160.4; 136.5; 136.2; 135.4; 129.9; 129.7; 129.5; 129.2;129.0; 128.9; 128.7; 127.2; 127.1; 116.2; 116.0; 115.6; 53.2; 52.5;49.8; 46.9; 44.0; 42.8; 40.9; 40.6; 40.4; 40.2; 40.0; 39.8; 39.6; 27.7;26.6.

Example 612-(4-Trifluoromethylphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH12²)

Procedure as 50ELH14B.

Reaction Step 0: 4-Trifluoromethylphenylacetyl chloride (50ELH12¹)

4-Trifluorophenylacetic acid (1.0 g) and thionyl chloride (15 ml) wererefluxed for 1 h. The excess thionyl chloride was evaporated off. NMRshowed complete conversion.

Reaction-Step 2:2-(4-Trifluoromethylphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH12²)

Starting materials: 50ELH4 (0.12 g, 0.55 mmol, 1.0 eq.),4-trifluoromethylphenylacetylchloride (50ELH12¹)(0.11 g, 0.5 mmol, 1.0eq.).

Product: Yield 47.1 mg (24%), UV/MS 96/96 (M⁺ 409), r_(t) (A, MS) 4.566,R_(f) 0.25 (3% MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, CDCl₃) δ 7.52 (d, 2H),7.22 (d, 2H), 7.17 (dd, 2H), 7.04 (t, 2H), 4.86 (brt, 1H), 4.58 (s, 2H),3.64 (s, 2H), 3.45 (brd, 2H), 2.84 (brq, 2H), 2.71 (d, 3H), 2.45 (brq,2H), 1.77 (brd, 2H). ¹³C-NMR 171.8; 163.6; 161.2; 138.7; 133.3; 129.8;129.5; 127.5; 127.4; 125.8; 125.7; 116.4; 116.2; 54.4; 48.9; 46.3; 43.6;40.8; 26.3.

Example 62 4-(4-Methoxybenzylamino)-1-methylpiperidine (50ELH18)

Procedure as 50ELH27.

Starting materials: 1-Methyl4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.),4-methoxybenzylamine (1.37 g, 1.0 eq.).

Product: UV/MS 95/95 (M⁺ 235), r_(t) (A, MS) 3.509. ¹H-NMR (400 MHz,CDCl₃) δ 7.3-6.8 (m, 4H), 3.77 (s, 3H), 3.73 (s, 2H), 2.86 (m, 2H), 2.55(m, 1H), 2.30 (s, 3H), 2.1 (t, 2H), 1.96 (dd, 2H), 1.50 (m, 2H).

Example 632-(4-Trifluoromethylphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH20A)

Procedure as 50ELH14B.

Reaction-Step 1: Methyl4-(N-[1-methylpiperidine-4-yl]aminomethyl)benzoate (50ELH19)

Starting materials: 1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.),methyl 4-(aminomethyl)benzoate hydrochloride (2.0 g, 1.0 eq.).

Product: UV/MS 81/88 (M⁺ 263), r_(t) (A, MS) 3.060. ¹H-NMR (400 MHz,CDCl₃) δ 8.00 (d, 2H), 7.20 (d, 2H), 3.90 (s, 3H), 3.85 (s, 2H), 2.96(dt, 2H), 2.7 (brs, 1H), 2.62 (m, 1H), 2.40 (s, 3H), 2.28 (t, 2H), 1.96(m, 2H), 1.56 (m, 2H).

Reaction-Step 2:2-(4-Trifluoromethylphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH20A)

Starting materials: 50ELH19 (0.20 g, 0.76 mmol, 1.0 eq.), 50ELH12¹(0.169 g, 1.0 eq.).

Product: Yield 108.9 mg (32%), UV/MS 100/100 (M⁺ 448), r_(t) (A, MS)3.327, R_(f) 0.3 (5% MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, DMSO, rotamers56/44) δ 10.7 and 10.4 (2brs, 1H), 7.96-7.28 (m, 8H), 4.70 and 4.51 (2s,2H), 4.30 (brt, 1H), 4.06 and 3.69 (2s, 2H), 3.83 and 3.81 (2s, 3H),3.00 (m, 2H), 2.63 (m, 3H), 2.05 (brt, J=12 Hz, 2H), 1.69 (brt, J=12 Hz,2H). ¹³C-NMR (CDCl₃) 171.9; 166.7; 142.9; 138.5; 130.7; 130.1; 129.7;126.2; 125.9; 55.2; 52.5; 49.2; 47.4; 41.2; 32.1; 26.6; 22.9; 14.3.

Example 642-Phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH20B)

Procedure as 50ELH14B

Reaction-Step 2:2-Phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH20B)

Starting materials: 50ELH19 (0.2 g, 0.76 mmol, 1.0 eq.),phenylacetylchloride (0.117 g, 1.0 eq.). Product: Yield 82.5 g (29%),UV/MS 100/100 (M⁺ 381), r_(t) (A, MS) 2.652, R_(f) 0.25 (3%MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, CDCl₃) δ 12.2 (brs, 1H), 8.00 (d, J=7.4,2H), 7.4-7.2 (m, 4H), 7.08 (d, J=7.4, 2H), 4.89 (brt, 1H), 4.62 (s, 2H),3.90 (s, 3H), 3.56 (s, 2H), 3.42 (d, J=11.0, 2H), 2.84 (q, J=11.0, 2H),2.68 (d, J=3.6, 3H), 2.40 (q, J=11.0, 2H), 1.77 (brd, J=11.0, 2H).¹³C-NMR 173.0; 168.0; 143.3; 136.7; 130.6; 129.0; 127.4; 125.9; 54.5;52.4; 48.8; 43.6; 41.4; 26.3.

Example 652-(4-Chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH20C)

Procedure as 50ELH14B.

Reaction-Step 2:2-(4-Chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH20C)

Starting materials: 50ELH19 (0.2 g, 0.76 mmol, 1.0 eq.),4-chlorophenylacetylchloride (0.131 g, 1.0 eq.).

Product: Yield 79.2 g (26%), UV/MS 100/96 (M⁺ 399), r_(t) (A, MS) 2.333.¹H-NMR (400 MHz, DMSO, rotamers 62/38) δ 10.8 and 10.60 (2brs, 1H), 7.95and 7.85 (2d, J=8.6, 2H), 7.4 and 7.28 (2d, 2H), 7.35 and 7.14 (2m, 4H),4.67 and 4.50 (2s, 2H), 4.29 (m, 1H), 3.93 and 3.84 (2s, 2H), 3.81 (s,3H), 3.21 (d, J=11.9, 2H), 3.00 (d, J=11.9, 2H), 2.63 (s, 3H), 2.06 (m,2H), 1.68 and 1.56 (d, J=11.9, 2H). ¹³C-NMR (CDCl₃) 172.6; 166.7; 163.4;161.0; 143.0; 130.7; 130.6; 130.5; 126.0; 115.9; 115.7; 54.7; 52.4;48.9; 46.9; 44.0; 40.4; 26.4.

Example 662-(4-Methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH20D)

Procedure as 50ELH14B.

Reaction-Step 2:2-(4-Methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH20D)

Starting materials: 50ELH19 (0.2 g, 0.76 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.140 g, 1.0 eq.).

Product: Yield 108.6 g (26%), UV/MS 100/99 (M⁺ 410), r_(t) (A, MS)2.280. ¹H-NMR (400 MHz, CDCl₃) δ 12.38 (brs, 1H), 8.00 (d, J=7.2, 2H),7.28 (d, J=7.2, 2H), 7.00 (d, J=7.2, 2H), 6.79 (d, J=7.2, 2H), 4.88(brt, 1H), 4.61 (s, 2H), 3.90 (s, 3H), 3.75 (s, 3H), 3.42 (brd, J=10.7,2H), 2.84 (q, J=10.7, 2H), 2.68 (d, J=3.6, 3H), 2.40 (brq, J=10.7, 2H),1.75 (d, J10.7, 2H). ¹³C-NMR 173.0; 166.8; 159.0; 143.3; 130.5; 129.9;129.8; 126.3; 125.9; 114.5; 55.5; 54.7; 52.4; 48.7; 46.7; 43.6; 40.6;32.1; 26.3; 22.9; 14.3.

Example 672-(4-TMethylphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH23)

Procedure as 50ELH14B.

Reaction-Step 2:1-Phenyl-N-[2-(4-methylphenyl)ethyl]-N-(1-methylpiperidin-4-yl)amide(50ELH23)

Starting materials: 4-(2-Phenylethyl)amino-1-methylpiperidine (0.20 g,0.86 mmol, 1.0 eq.), benzoylchloride (0.158 g, 1.0 eq.).

Product: Yield 159 mg (50%), UV/MS 100/100 (M⁺ 337), r_(t) (A, MS)3.289, R_(f) 0.55 (10% MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, DMSO (80° C.)) δ10.9 (brs, 1H), 7.44 (s, 2H), 7.34 (d, J=3.0 Hz, 2H), 7.04 (d, J=7.0 Hz,2H), 6.95 (brs, 2H), 4.00 (brs, 1H), 3.40 (d, J=4.2 Hz, 2H), 3.35 (d,J=4.2 Hz, 2H), 2.95 (brs, 2H), 2.77 (t, J=3.2 Hz, 2H), 2.40 (q, J=6.4Hz, 2H), 2.24 (s, 3H) 1.83 (d, J=6.4 Hz, 2H). ¹³C-NMR (CDCl₃) 171.6;138.1; 136.3; 136.0; 129.8; 129.6; 129.1; 129.1; 126.7; 53.6; 52.4;46.1; 42.9; 35.9; 27.3; 21.1.

Example 682-(4-Methoxyphenyl)-N-(3-phenyl-1-propyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH65)

Procedure as 50ELH14B.

Reaction-Step 1: 4-(3-Phenylaminopropyl)piperidine (50ELH59)

Starting materials: 1-Methyl-4-piperidone (1.1 ml, 7.4 mmol, 1.0 eq.),3-phenylpropylamine (1.35 g, 1.0 eq.).

Product: UV/MS 100/94 (M⁺ 233), r_(t) (A, MS) 3.534.). ¹H-NMR (400 MHz,CDCl₃) δ 7.28-7.12 (m, 5H), 3.40 (brs, 1H), 2.84 (dt, J=12.3 and 3.5 Hz,2H), 2.64 (q, J=7.0 Hz, 4H), 2.51 (m, 1H), 2.27 (s, 3H), 2.05 (brt,J=12.3 Hz, 2H), 1.82 (m, 2H), 1.44 (m, 2H).

Reaction-Step 2:2-(4-Methoxyphenyl)-N-(3-phenyl-1-propyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH65)

Starting materials: 50ELH59 (0.50 g, 2.2 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.398 g, 1.0 eq.).

Product: Yield 153 mg (43%), UV/MS 100/100 (M⁺ 381), r_(t) (A, MS)2.938. ¹H-NMR (400 MHz, DMSO, rotamers 55/45) δ 11.0 and 10.90 (2brs,1H), 7.30-7.10 (m, J=7.9 Hz, 6H), 6.97 (d, J=7.9 Hz, 1H), 4.22 and 4.06(2dt, dH), 3.70 (s, 3H), 3.35 (t, J=10.4 Hz, 2H), 3.15 (m, 2H), 3.00 (q,J=10.4 Hz, 2H), 2.66 (d, 3H), 2.52 (q, J=7.9 Hz, 2H), 2.17 (brq, J=12Hz, 2H) 1.73 (m, 2H), 1.70 and 1.52 (2d, J=12 Hz, 2H), ¹³C-NMR (DMSO)171.3; 171.0; 158.6; 142.2; 141.7; 130.0; 129.0; 128.0; 128.5; 128.2;126.6; 114.5; 55.7; 55.7; 53.5; 53.3; 50.1; 44.5; 42.9; 41.9; 33.7;33.1; 32.9; 31.4; 27.8; 26.8.

Example 692-(4-Methoxyphenyl)-N-[2-(4-methylphenyl)ethyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH68)

Procedure as 50ELH14B

Reaction-Step 1: 4-[2-(4-Methylphenyl)ethylamino]-piperidin (50ELH58)

Starting materials: 1-Methyl4-piperidone (1.1 ml, 7.4 mmol, 1.0 eq.),2-(4-methylphenyl)ethylamine (1.0 g, 1.0 eq.).

Product: UV/MS 100/91 (M⁺ 233), r_(t) (A, MS) 3.933.). ¹H-NMR (400 MHz,CDCl₃) δ 7.4 (s, 5H), 3.27 (brs, 1H), 2.84 (d, J=7.0 Hz, 4H), 2.75 (m,2H), 2.54 (m, 1H), 2.29 (2xs, 6H), 2.10 (brt, J=12.3 Hz, 2H), 1.86 (brd,2H), 1.45 (m, 2H).

Reaction-Step 2:2-(4-Methoxyphenyl)-N-[2-(4-methylphenyl)ethyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH68)

Starting materials: 50ELH58 (0.30 g, 1.3 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.238 g, 1.0 eq.).

Product: Yield 125 mg (26%), UV/MS 100/99 (M⁺ 381), r_(t) (A, MS) 3.156.¹H-NMR (400 MHz, DMSO, rotamers 50/50) δ 11.0 and 10.90 (2brs, 1H),7.25-7.04 (m, J=8.7 Hz, 6H), 6.87 and 6.84 (2d, J=8.7 Hz, 2H), 4.30 and4.09 (2dt, J=11.5 Hz, dH), 3.73 and 3.58 (2s, 2H), 3.71 and 3.70 (2s,3H), 3.35 (m, (Underneath waterpeak) 3H), 3.24 (m, 1H), 3.02 (m, J=11.5Hz, 2H), 2.80-2.62 (m, 5H), 2.32 and 2.20 (2q, J=11.5 Hz, 2H), 2.26 and2.24 (2s, 3H) 1.78 and 1.49 (2d, J=11.5 Hz, 2H). ¹³C-NMR (DMSO) 171.5;171.2; 158.6; 136.8; 136.2; 136.0; 135.8; 130.7; 130.5; 129.7; 129.6;129.4; 129.2; 128.4; 128.3; 114.5; 55.8; 55.7; 53.3; 53.3; 52.2; 50.2;46.8; 43.9; 42.9; 36.8; 35.2; 27.6; 26.8; 21.3.

Example 702-(4-Methoxyphenyl)-N-[2-(2-thionyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH71A)

Procedure as 50ELH14B

Reaction-Step 1: 4-[2-(2-Thienyl)ethylamino]piperidin (50ELH67A)

Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.),thiophene-2-ethylamine (0.563 g, 1.0 eq.).

Product: UV/MS 94/93 (M⁺ 225).

Reaction-Step 2:2-(4-Methoxyphenyl)-N-[2-(2-thienylethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH71A)

Starting materials: 50ELH67A (0.243 g, 1.08 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.2 g, 1.0 eq.).

Product: Yield 80.7 mg (33%), UV/MS 100/100 (M⁺ 373), r_(t) (A, MS)2.613. ¹H-NMR (400 MHz, DMSO, rotamers 50/50) δ 10.8 and 10.6 (2brs,1H), 7.36 and 7.31 (2d, J=4.7 Hz, 1H), 7.20 and 7.06 (2d, J=8.3 Hz, 2H),7.00-6.92 (m, J=4.7 and 2.8 Hz, 2H), 6.87 and 6.40 (2d, J=8.3 Hz, 2H),4.22 and 4.08 (2dt, J=12.2 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 2H),3.46-3.30 (m, 4H), 3.10-2.90 (m, 4H), 2.67 (m, 2H), 2.28 and 2.12 (2q,J=12 Hz, 2H), 1.80 and 1.50 (2d, J=12 Hz, 2H). ¹³C-NMR (DMSO) 172.5;158.9; 139.6; 130.0; 129.6; 126.8; 124.5; 114.5; 55.5; 54.7; 49.3; 45.8;43.8; 41.3; 31.9; 29.9

Example 712-(4-Methoxyphenyl)-N-[2-(4-nitrophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH71C)

Procedure as 50ELH14B

Reaction-Step 1: 4-[2-(4-nitrophenyl)ethylamino]-piperidin (50ELH67C)

Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.),4-nitrophenyl-2-ethylamine (0.897 g, 1.0 eq.).

Product: UV/MS 96/89 (M⁺ 264), r_(t) (A, MS) 3.264.

Reaction-Step 2:2-(4-Methoxyphenyl)-N-[2-(4-nitrophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH71A)

Starting materials: 50ELH67C (0.285 g, 1.08 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.2 g, 1.0 eq.).

Product: Yield 130.9 mg (30%), UV/MS 100/100 (M⁺ 412), r_(t) (A, MS)2.219. ¹H-NMR (400 MHz, DMSO, rotamers 50/50) δ 10.8 and 10.6 (2brs,1H), 8.17 and 8.12 (2d, J=8.6 Hz, 2H), 7.58 and 7.48 (2d, J=8.6 Hz, 2H),7.2 and 7.1 (2d, J=8.6 Hz, 2H), 6.87 and 6.40 (2d, J=8.6 Hz, 2H), 4.25and 4.10 (2dt, J=12 Hz, 1H), 3.72 (s, 3H), 3.70 (s, 2H), 3.48-3.30 (m,4H), 3.10-2.84 (m, 4H), 2.69 and 2.67 (2d, J=4.7 Hz, 3H), 2.34 and 2.15(2q, J=13.2 Hz, 2H), 1.79 and 1.47 (2d, J=13.2 Hz, 2H).

Example 722-(4-Methoxyphenyl)-N-(2-thienylmethyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH73A)

Procedure as 50ELH14B.

Reaction-Step 1: 4-[(2-Thienylmethyl)amino]-1-methylpiperidine(50ELH66A)

Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.),2-thienylmethylamine (0.52 g, 1.0 eq.).

Product: UV/MS 77/86 (M⁺ 211), r_(t) (A,MS) 2.739.

Reaction-Step 2:2-(4-Methoxyphenyl)-N-(2-thienylmethyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH73A)

Starting materials: 50ELH66A (0.228 g, 1.08 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.2 g, 1.0 eq.).

Product: Yield 178.4 mg (50%), UV/MS 100/98 (M⁺ 359), r_(t) (A, MS)3.117. ¹H-NMR (400 MHz, DMSO) δ 10.9 and 10.6 (2brs, 1H), 7.47 and 7.32(2d, J=4.5 Hz, 1H), 7.20 and 7.03 (2d, J=8.4 Hz, 2H), 7.03 and 6.98 (2m,1H), 6.87 (m, 3H), 4.70 and 4.57 (2s, 2H), 4.42 and 4.16 (2t, J=11.9 Hz,1H), 3.77 and 3.60 (2s, 2H), 3.51 (s, 3H), 3.15 (m, 2H), 2.98 (m, J=11.9Hz, 2H), 2.65 (2d, J=4.5 Hz, 3H), 2.25 and 2.17 (2q, J=11.9 Hz, 2H),1.69 and 1.44 (2d, J=11.9 Hz, 2H). ¹³C-NMR (DMSO) 171.4; 158.6; 143.2;130.7; 128.1; 126.6; 126.3; 125.9; 114.5; 55.7; 53.3; 52.6; 50.0; 42.8;27.7; 26.8.

Example 732-(4-Methoxyphenyl)-N-(furfuryl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH73B)

Procedure as 50ELH14B.

Reaction-Step 1: 4-(Furfurylamino)-1-methylpiperidin (50ELH66B)

Starting materials: 1-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.),Furfurylamine (0.43 g, 1.0 eq.).

Product: UV/MS 77/92 (M⁺ 195), r_(t) (A, MS) 2.812.).

Reaction-Step 2:2-(4-Methoxyphenyl)-N-(furfuryl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH73B)

Starting materials: 50ELH66B (0.21 g, 1.08 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.2 g, 1.0 eq.).

Product: Yield 134 mg (36%), UV/MS 100/99 (M⁺ 343), r_(t) (A, MS) 2.401.¹H-NMR (400 MHz, DMSO, rotamers 57/43) δ 10.95 and 10.75 (2brs, 1H),7.63 and 7.48 (s, 1H), 7.18 and 7.06 (2d, J=7.7 Hz, 2H), 6.85 (t, J=7.7Hz, 2H), 6.44 and 6.33 (2d, J=7.7 Hz, 1H), 6.37 and 6.11 (2s, 1H) 4.5and 4.34 (2s, 2H), 4.42 and 4.18 (2dt, J=11 and 2 Hz, 1H), 3.75 and 3.65(2s, 2H) 3.70 (s, 3H), 3.33 (hidden, 2H), 3.0 (q, 2H); 2.64 (d, J=4.7Hz, 3H), 2.15 (dq, J=11 and 2 Hz, 2H), 1.65 and 1.50 (2d, J=11 Hz, 2H).

Example 742(2-thienylmethyl)-N-(4-methylphenylmethyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH82)

Procedure as 50ELH14B

Reaction-Step 2:2-(2-thienylmethyl)-N-(4-methylphenylmethyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH82)

Starting materials: 50ELH25 (0.30 g, 1.38 mmol, 1.0 eq.),thiophene-2-acetylchlorid (0.22 g, 1.0 eq.).

Product: Yield 235 mg (62%), UV/MS 97/93 (M⁺ 343), r_(t) (A, MS) 2.795.¹H-NMR (400 MHz, DMSO, rotamers 54/46) δ 10.8 and 10.60 (2brs, 1H), 7.4and 7.35 (2d, 1H), 7.2-6.76 (m, 6H), 4.55 and 4.4 (2s, 2H), 4.49 and4.26 (2dt, J−11 and 2 Hz, 2H), 4.15 and 3.79 (2s, 2H), 3.32 (d, J=l 1Hz, 2H), 2.99 (q, 2H), 2.63 (s, 3H), 2.27 and 2.23 (2s, 3H), 2.09 (q,J=11 Hz, 2H), 1.66 and 1.55 (2d, J=11 Hz, 2H).

Example 752-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclopentylpiperidin-4-yl)acetamide(42ELH75)

Procedure as for 42ELH80, except that the reaction was run at 60° C. for3 days.

Starting materials: 50ELH87 (0.25 g, 0.71 mmol, 1.0 eq.),Cyclopentylbromide (0.288 g, 3.0 eq.).

Product: Yield 91.2 mg (34%), UV/MS 88/93 (M⁺ 421), r_(t) (A, MS) 4.450.

Example 762-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-(3-(1,3-dihydro-2H-benzimidazol-2-one-1-yl)propyl)piperidine-4-yl)acetamide(50ELH89)

50ELH87 (0.05 g, 0.14 mmol, 1 eq.) was transferred to a 4 ml vial anddissolved in 1 ml of acetonitrile. Then,1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.032 g, 1.1 eq.),sodium carbonate (0.022 g, 1.1 eq.) and KI (one crystal) were added andthe vial was sealed and shaken for 20 h at 82° C. The mixture wasextracted with distilled water (pH 10, sodium carbonate) anddichloromethane (3 times) the organic layers were dried with sodiumsulfate and concentrated. The title compound was purified by HPLC andevaporated to dryness, forming a trifluoroacetic acid salt. Yield 8.8 mg(12%). UV/MS 100/100 (M⁺ 527), r_(t) (A, MS) 2.851.

Example 772-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-methylthiazol-4-ylmethyl)piperidin-4-yl]acetamide(63ELH1A)

50ELH87 (0.3 g, 0.852 mmol, 1.0 eq) and⁴-(chloromethyl)-2-methylthiazole hydrochloride (0.235 g, 1.5 eq) wereadded to a 7 ml vial and dissolved in acetonitrile (3 ml). Potassiumcarbonate (141.3 g, 1.2 eq) and a crystal of potassium iodide were addedand the vial was sealed and shaken for 20 h at 82° C. The reactionmixture was extracted with distilled water (made basic by potassiumcarbonate, pH 10) and dichloromethane. The crude product was dried withsodium sulfate and concentrated. After purification by HPLC the productwas converted into the hydrochloride salt by dissolving the free base in1 ml dichloromethane and adding 1 eq. HCl in ether (2M). This mixturewas added drop-wise to an excess of heptane where the productprecipitated. The solvent was removed by evaporation leaving a whitepowder as the product. yield 83.8 mg (21%), UV/MS 100/90 (M⁺ 463), r_(t)(B, MS) 11.82.

Example 782-(4-Methoxyphenyl)-N-(24-(fluorophenyl)ethyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH93A)

Procedure as 50ELH14B.

Reaction-Step 1: 4-[2-4-(Fluorophenyl)ethylamino]-1-methylpiperidine(50ELH92A)

Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.),4-(fluorophenyl)ethylamine (0.369 g, 1.0 eq.).

Product: UV/MS 60/92 (M⁺ 237), r_(t) (A,MS) 3.422.

Reaction-Step 2:2-(4-Methoxyphenyl)-N-(2-4-(fluorophenyl)ethyl)-N-(1-methylpiperidin-4-yl)acetamide(50ELH93A)

Starting materials: 50ELH92A (0.625 g, 2.65 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).

Product: Yield 181 mg (18%), UV/MS 87/97 (M⁺ 385), r_(t) (A, MS) 2.783.R_(f) 0.8 (10% MeOH/CH₂Cl₂). ¹H-NMR (400 MHz, DMSO, rotamers 50/50) δ10.9 (brs, 1H), 7.56-6.8 (m, 8H), 4.26 and 4.02 (2brt, 2H), 3.70 and3.95 (2s, 3H), 3.59 and 3.57 (2s, 2H), 3.4-3.15 (m, 5H), 2.96-2.66 (m,5H), 2.62 and 2.56 (2s, 3H), 2.29 and 2.10 (2q, 2H), 1.73 and 1.41 (2d,2H). ¹³C-NMR (DMSO) 172.5; 171.4; 171.3; 162.9; 162.7; 160.5; 160.3;158.9; 158.6; 136.1; 136.1; 135.3; 131.4; 131.3; 131.1; 131.0; 131.0;130.6; 130.5; 128.4; 128.4; 126.9; 115.9; 115.8; 115.7; 115.6; 114.5;55.7; 53.7; 53.5; 52.7; 52.3; 50.7; 46.7; 43.8; 43.2; 43.0; 36.3; 34.7;27.9; 26.9.

Example 792-(4-Methoxyphenyl)-N-[2-(2,5-dimethoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH93C)

Procedure as 50ELH14B. A small amount was purified by HPLC andevaporated to dryness, forming the trifluoroacetic acid salt.

Reaction-Step 1:4-[2-(2.5-dimethoxyphenyl)ethylamino]-1-methylpiperidine (50ELH92A)

Starting materials: Methyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.),2,5-(dimethoxyphenyl)ethylamine (0.481 g, 1.0 eq.).

Product: UV/MS 81/90 (M⁺ 279), r_(t) (A,MS) 2.868.

Reaction-Step 2:2-(4-Methoxyphenyl)-N-[2-(2,5-dimethoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH93C)

Starting materials: 50ELH93C (0.737 g, 2.65 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).

Product: UV/MS 82/100 (M⁺ 427), r_(t) (B, MS) 8.44. R_(f) 0.8 (10%MeOH/CH₂Cl₂).

Example 802-(4-Methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH93D)

Procedure as 50ELH14B, but purified by HPLC and evaporated to drynessforming the trifluoroacetic acid salt.

Reaction-Step 1: 4-[2-(2,4-Dichlorophenyl)ethylamino]-1-methylpiperidine(50ELH92D)

Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.),2,5-(dichlorophenyl)ethylamine (0.50 g, 1.0 eq.).

Product: UV/MS 82/92 (M⁺ 287), r_(t) (A,MS) 4.875.

Reaction-Step 2:2-(4-Methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH93D)

Starting materials: 50ELH93D (0.76 g, 2.65 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).

Product: UV/MS 100/96 (M⁺ 435), r_(t) (A, MS) 4.415. R_(f) 0.8 (10%MeOH/CH₂Cl₂).

Example 812-(4-Methoxyphenyl)-N-[2-(3-chlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH93E)

Procedure as 50ELH14B, but purified on HPLC and evaporated to drynessforming the trifluoroacetic acid salt.

Reaction-Step 1: 4-[(3-Chlorophenyl)ethyl)amino-1-methylpiperidine(50ELH92E)

Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.),3-(chlorophenyl)ethylamine (0.413 g, 1.0 eq.).

Product: UV/MS 86/88 (M⁺ 253), r_(t) (A,MS) 3.175.

Reaction-Step 2:2-(4-Methoxyphenyl)-N-[2-(3-chlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH93E)

Starting materials: 50ELH93E (0.67 g, 2.65 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).

Product: UV/MS 100/100 (M⁺ 401), r_(t) (A, MS) 3.464. R_(f) 0.8 (10%MeOH/CH₂Cl₂).

Example 822-(4-Methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH95B)

Procedure as 50ELH14B. Purified by HPLC and evaporated to drynessforming the trifluoroacetic acid salt.

Reaction-Step 1: 4-[(4-Methoxyphenyl)ethyl)amino]-1-methylpiperidine(50ELH94B)

Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.),4-methoxyphenylethylamine (0.40 g, 1.0 eq.).

Product: UV/MS 74/87 (M⁺ 249), r_(t) (A,MS) 2.935.

Reaction-Step 2:2-(4-Methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH95B)

Starting materials: 50ELH94B (0.657 g, 2.65 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).

Product: UV/MS 100/100 (M⁺ 397), r_(t) (A, MS) 2.389. R_(f) 0.8 (10%MeOH/CH₂Cl₂).

Example 832-(4-Methoxyphenyl)-N-[2-(3-fluorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH95D)

Procedure as 50ELH14B. Purified on HPLC and evaporated to dryness,forming the trifluoroacetic acid salt.

Reaction-Step 1: 4-[2-((3-Fluorophenyl)ethyl)amino]-1-methylpiperidine(50ELH94D)

Starting materials: 1-Methyl4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.),3-fluorophenylethylamine (0.369 g, 1.0 eq.).

Product: UV/MS 74/89 (M⁺ 237), r_(t) (A,MS) 2.946.

Reaction-Step 2:2-(4-methoxyphenyl)-N-[2-(3-fluorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(50ELH95D)

Starting materials: 50ELH94D (0.625 g, 2.65 mmol, 1.0 eq.),4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).

Product: UV/MS 100/95 (M⁺ 385), r_(t) (A, MS) 2.946. R_(f) 0.8 (10%MeOH/CH₂Cl₂).

Example 842-(4-ethoxyphenyl)-N-[2-(4-fluorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(63ELH20) Reaction Step 1: 4-Ethoxyphenylacetic acid chloride(63ELH19)

4-Ethoxyphenylacetic acid (0.5 g, 2.8 mmol) was transferred to a 7 mlvial and dissolved in thionylchloride (3 ml). The reaction mixture wasshaken at 70° C. for 2½ hours. Thionylchloride was evaporated off andthe resulting product was used unpurified.

Reaction step 2:2-(4-Ethoxyphenyl)-N-[2-(4-fluorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide(63ELH20)

63ELH17 (0.11 g, 0.47 mmol) was transferred to a 4 ml vial and dissolvedin dichloromethane. 63ELH19 (0.084 mg, 1 eq.) was added and the vial wassealed and the reaction shaken for 20 h. The product was extracted indistilled water (made basic with potassium carbonate, pH 10) anddichloromethane. Dried with sodium sulfate and concentrated. Purified byHPLC. The extraction, drying and concentration was repeatedand theproduct re-dissolved in dichloromethane (1 ml) and HCl (1 eq., 2 M inether) was added. The mixture was added drop-wise to an excess ofheptane whereupon the salt precipitated. Yield 33.4 mg (18%), UV/MS:92/100 (M⁺ 399), t_(r) (B, MS) 10.38.

Example 852-(4-Ethoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide(63ELH21)

50ELH4 (0.11 g, 0.49 mmol, 1.0 eq.) was transferred to a 4 ml vial anddissolved in dichloromethane. 63ELH19 (0.089 mg, 1.0 eq.) was added andthe vial was sealed and the reaction shaken for 20 h. The product wasextracted in distilled water (made basic with potassium carbonate, pH10) and dichloromethane. Dried with sodium sulfate and concentrated.Purified by HPLC. The extraction, drying and concentration was repeatedand the product dissolved in dichloromethane (1 ml) and HCl (1 eq., 2 Min ether) is added. This mixture was added drop-wise to an excess ofheptane whereupon the salt precipitated. Yield 31.1 mg (16%), UV/MS:94/100 (M⁺ 385), t_(r) (A, MS) 2.573.

Example 86N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(3-hydroxy4-methoxyphenyl)acetamide(57MBT12B)

N-((4-methylphenyl)methyl)-4-amino-1-methylpiperidine (50ELH25) (105 mg,0.48 mmol) and 3-hydroxy-4-methoxyphenylacetic acid (88 mg, 0.48 mmol)were dissolved in DMF (10 ml). Diisopropylethylamine (DIEA, 250 μL, 1.44mmol) was added followed by bromo-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBrOP, 336 mg, 0.72 mmol), and the mixture wasstirred at r.t for 1 h. Water (50 mL) was added, and the reactionmixture was extracted with EtOAc (2×50 mL). Drying by Na₂SO₄ andconcentration yielded 514 mg crude material, which was purified by flashchromatography (0-30% MeOH in CH₂Cl₂). This gave 105 mg (57%) of thetitle compound as a white solid. R_(f)=0.20 (10% MeOH in CH₂Cl₂).HPLC-MS (method A) showed MH⁺=383. UV/MS(%)=100/92. ¹H-NMR (400 MHz,CD₃OD, Rotamers 52:48): δ 7.18-6.58 (m, 7H), 4.53 (s, 2H), 4.31 and 3.97(2m, 1H), 3.82 and 3.81 (2s, 3H), 3.80 and 3.55 (2s, 2H), 3.04 and 2.85(2m, 2H), 2.41 and 2.32 (2s, 3H), 2.35 and 2.12 (2m, 2H), 2.29 and 2.27(2s, 3H), 1.83 and 1.74 (2m, 2H), 1.72 and 1.33 (2m, 2H)

Example 87N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(3,4-dihydroxyphenyl)acetamide(57MBT24B)

N-((4-methylphenyl)methyl)-N-(1-methylpiperidine-4-yl)-2-(3-hydroxy-4-methoxyphenyl)acetamide(57MBT12B) (52 mg, 0.136 mmol) was dissolved in CH₂Cl₂ (1 mL) and cooledto −78° C. Boron tribromide (1M in CH₂Cl₂, 204 μl, 0.204 mmol) was addeddropwise and the cooling bath was removed. After stirring for 2 h,methanol (2 mL) was added and the mixture was evaporated. The resultingoil was purified by preparative HPLC to give 24 mg (48%) of the titlecompound as a white solid. HPLC-MS (method A) showed MH⁺=369.UV/MS(%)=100/97. ¹H-NMR (400 MHz, CD3OD, Rotamers 33:67): δ 7.19-6.47(m, 7H), 4.54 and 4.53 (2s, 2H), 4.23 (m, 1H), 3.83 and 3.58 (2s, 2H),3.46 and 3.40 (2br d, J=12 Hz, 2H), 3.02 and 2.95 (2br t, J=12 Hz, 2H),2.79 (s, 3H), 2.33 and 2.28 (2s, 3H), 2.17 and 1.84 (2dg, J=4, 12 Hz,2H), 1.87 and 1.48 (2br d, J=12 Hz, 2H)

Example 88N-((3-hydroxy4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methoxyphenyl)acetamide(57MBT54B)

N-((4-methoxyphenyl)methyl)-4-amino-1-methylpiperidine (1 g, 4.27 mmol)was dissolved in 4% formic acid in methanol (60 mL). 10% Pd/C (1 g) wasadded under argon and the reaction mixture was heated to reflux for 24h. The mixture was filtered through celite and the filtrate wasacidified with conc. HCl to pH 1. Concentration yielded a yellow oilwhich was purified by flash chromatography (MeOH/CH₂Cl₂ 3:7+3.5% NH₄OH)to give 249 mg (51%) of 4-amino-1-methylpiperidine (57-MBT36B) as awhite solid. R_(f)=0.13 (10% MeOH in CH₂Cl₂+3.5% NH₄OH). HPLC-MS (methodB) showed MH⁺=115. UV/MS(%)=−/100.

4-Amino-1-methylpiperidine (57MBT36B) (26 mg, 0.231 mmol) was dissolvedin methanol (1 mL) and 3-hydroxy-4-methylbenzaldehyde (32 mg, 0.231mmol) and acetic acid (33 μL) were added. The mixture was cooled to 0°C. NaBH₃CN (29 mg, 0.462 mmol) was added and the cooling bath wasremoved. After 3 h the reaction mixture was evaporated and flashchromatography (0-30% MeOH in CH₂Cl₂) gave 27 mg (50%) ofN-((3-hydroxy-4-methylphenyl)methyl)-4-amino-1-methylpiperidine(57MBT44C) as a white solid. R_(f)=0.27 (10% MeOH in CH₂Cl₂+3.5% NH₄OH).HPLC-MS (method A) showed MH⁺=235. UV/MS(%)=99/99.

N-((3-hydroxy-4-methylphenyl)methyl)-4-amino-1-methylpiperidine(57MBT44C) (27 mg, 0.115 mmol) was dissolved in CH₂Cl₂ (2 mL).4-Methoxyphenylacetyl chloride (17 μL, 0.115 mmol) was added dropwiseunder argon. After 3 h, n-heptane (3 mL) was added and the mixture wasevaporated. Flash chromatography (0-20% MeOH in CH₂Cl₂) gave 14 mg (32%)of the title compound as a white solid. R_(f)=0.32 (10% MeOH inCH₂Cl₂+3.5% NH₄OH). HPLC-MS (method A) showed MH⁺=383. UV/MS(%)=99/96.¹H-NMR (400 MHz, CD₃OD, Rotamers 63:37): δ 7.28-6.55 (m, 7H), 4.48 (s,2H), 4.37 and 3.95 (2m, 1H), 3.78 and 3.77 (2s, 3H), 3.06 and 2.89 (2brd, J=12 Hz, 2H), 2.42 and 2.32 (2s, 3H), 2.40 and 2.12 (2m, 2H), 2.18and 2.12 (2s, 3H), 1.86 and 1.83 (2m, 2H), 1.75 and 1.35 (2br d, J=12Hz, 2H)

Example 89N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-bromophenyl)acetamidehydrochloride(57MBT70-1D)

4-Bromophenylacetic acid (54 mg, 0.252 mmol) was dissolved in CH₂Cl₂ (2mL), and N-((4-methylphenyl)methyl)-4-amino-1-methylpiperidine (292mg/mL stock solution in CH₂Cl₂, 171 μL, 0.229 mmol) and polystyrenesupported diisopropylethylamine (PS-DIEA with a loading of 3.57 mmol/g,192 mg, 0.687 mmol) was added followed bybromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 160mg/mL stock solution, 1 mL, 0.334 mmol). The reaction mixture was shakenfor 1 h at r.t. and filtered onto a prewashed (methanol) ion exchangecolumn (0.88 mmol/g, 1 g). The column was washed with methanol (8*4 mL)and the remaining product was eluted off the column with 10% NH₄OH inmethanol (2*4 mL) and evaporated. The resulting oil was filtered throughsilica (H=4 cm, D=1 cm) with methanol/CH₂Cl₂ 1:9 (20 mL), evaporated andsubjected to a second ion exchange column (0.88 mmol/g, 1 g). The columnwas washed with methanol (8*4 mL) and the remaining product was elutedoff the column with 10% NH₄OH in methanol (2*4 mL) and evaporated onrotavap and oil pump. The product was dissolved in CH₂Cl₂ (0.5 mL) andHCl in diethylether (1.0 M, 0.1 mL, 0.1 mmol) was added. The solutionwas added to n-heptane (3 mL) and evaporation afforded 29 mg (25%) ofthe title compound as a white solid. R_(f)=0.31 (10% MeOH in CH₂Cl₂).HPLC-MS (method B) showed MH⁺=416. UV/MS(%)=100/99.

Example 90N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-iodophenyl)acetamidehydrochloride(57MBT70-2D)

The title compound was prepared according to example MBT04. Yield: 33 mg(26%). R_(f)=0.31 (10% MeOH in CH₂Cl₂). HPLC-MS (method B) showedMH⁺=463. UV/MS(%)=100/98.

Example 91N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-(2-propyl)phenyl)acetamidehydrochloride(57MBT70-3D)

The title compound was prepared according to example MBT04. Yield: 36 mg(34%). R_(f)=0.31 (10% MeOH in CH₂Cl₂). HPLC-MS (method B) showedMH⁺=379. UV/MS(%)=100/97.

Example 92N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-trifluoromethoxyphenyl)acetamidehydrochloride(57MBT70-4D)

The title compound was prepared according to example MBT04. Yield: 35 mg(30%). R_(f)=0.27 (10% MeOH in CH₂Cl₂). HPLC-MS (method B) showedMH⁺=421. UV/MS(%)=100/99.

Example 93N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methylthiophenyl)acetamidehydrochloride(57MBT70-5D)

The title compound was prepared according to example MBT04. Yield: 35 mg(33%). R_(f)=0.30 (10% MeOH in CH₂Cl₂). HPLC-MS (method B) showedMH⁺=383. UV/MS(%)=100/99.

Example 94N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-(N,N-dimethylamino)phenyl)acetamidehydrochloride(57MBT70-6D)

The title compound was prepared according to example MBT04.

Yield: 16 mg (15%). R_(f)=0.25 (10% MeOH in CH₂Cl₂). HPLC-MS (method A)showed MH⁺=380. UV/MS(%)=100/100.

Example 95N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-nitrophenyl)acetamidehydrochloride(57MBT70-7D)

The title compound was prepared according to example MBT04. Yield: 28 mg(27%). R_(f)=0.27 (10% MeOH in CH₂Cl₂). HPLC-MS (method B) showedMH⁺382. UV/MS(%)=100/100.

Example 96N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methoxy-3-methylphenyl)acetamidehydrochloride(57MBT70-8D)

The title compound was prepared according to example MBT04. Yield: 34 mg(32%). R_(f)=0.30 (10% MeOH in CH₂Cl₂). HPLC-MS (method B) showedMH⁺=381. UV/MS(%)=100/99.

Example 97N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-pyridyl)acetamidehydrochloride(57MBT70-9F)

The title compound was prepared according to example MBT04. Yield: 18 mg(17%). R_(f)=0.09 (10% MeOH in CH₂Cl₂). HPLC-MS (method A) showedMH⁺=338. UV/MS(%)=100/100.

Example 98N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methylphenyl)acetamidehydrochloride(57MBT62B)

The title compound was prepared according to example MBT04. Yield: 10 mg(35%). R_(f)=(10% MeOH in CH₂Cl₂). HPLC-MS (method A) showed MH⁺=351.UV/MS(%)=100/100.

Example 99N-((4-(hydroxymethyl)phenyl)methyl)-N-(1-methylpiperidin-4-yl)-2-(4-methoxyphenyl)acetamidehydrochloride(5 7MBT72D)

To a stirred suspension of LiAlH₄ (285 mg, 7.52 mmol) in diethylether(10 mL) at 0° C. was added a solution of 4-cyanobenzyl alcohol (0.5 g,3.76 mmol) in diethylether (5 mL) over 15 min. The grey reaction mixturewas heated to reflux for 3 h. After cooling to r.t., the mixture wastreated successively with water (1 mL), 2M NaOH (2 mL) and water (2 mL)under vigorous stirring. The resulting white slurry was filtered andwashed with CH₂Cl₂ (20 mL). Extraction with additional CH₂Cl₂ (20 ML)and n-butanol (20 mL) and evaporation yielded an oil, which upon flashchromatography (0-15% MeOH in CH₂Cl₂) gave 152 mg (29%) of4-(aminomethyl)benzylalcohol (57MBT52B) as a white solid. R_(f)−0.51(30% MeOH in CH₂Cl₂+3.5% NH₄OH).

1-Methyl-4-piperidone (84 μL, 0.73 mmol) was dissolved in methanol (5mL) and 4-(aminomethyl)benzylalcohol (57MBT52B) (100 mg, 0.73 mmol) wasadded followed by acetic acid (125 μL). NaBH₃CN (92 mg, 1.46 mmol) wasadded and the mixture was stirred for 3 h. The reaction mixture wasevaporated and 2M NaOH (5 mL) was added. Extraction with CH₂Cl₂ (4*5mL), drying with Na₂SO₄ and evaporation gave 152 mg (87%) ofN-((4-(hydroxymethyl)phenyl)methyl)-4-amino-1-methylpiperidine(57MBT56D) as a white solid. HPLC-MS (method B) showed MH⁺=235.UV/MS(%)=100/100.

N-((4-(Hydroxymethyl)phenyl)methyl)-4-amino-1-methylpiperidine(57MBT56D) (20 mg, 0.0853 mmol) was dissolved in CH₂Cl₂ (2 mL) and4-methoxyphenylacetyl chloride (26 μL, 0.171 mmol) was added dropwise.The reaction mixture was stirred for 1 h and water (500 μL) was addedfollowed by evaporation. A solution of sodium (5 mg, 0.179 mmol) inmethanol (2 mL) was added. After stirring for 4 h, the solution wastransferred to a prewashed (methanol) ion exchange column (0.88 mmol/g,1 g) and washed with methanol (4*4 mL). The remaining product was elutedoff the column with 10% NH₄OH in methanol (2*4 mL) and evaporated. Theresulting oil was filtered through silica (H=4 cm, D=1 cm) withmethanol/CH₂Cl₂ 2:8 (20 mL), evaporated and subjected to a second ionexchange column (0.88 mmol/g, 1 g). The column was washed with methanol(8*4 mL) and the remaining product was eluted off the column with 10%NH₄OH in methanol (2*4 mL) and evaporated on rotavap and oilpump. Theproduct was dissolved in CH₂Cl₂ (0.5 mL) and HCl in diethylether (1.0 M,0.1 mL, 0.1 mmol) was added. The solution was added to n-heptane (3 mL)and evaporation afforded 14 mg (39%) of the title compound as a whitesolid. R_(f)=0.16 (10% MEOH in CH₂Cl₂). HPLC-MS (method B) showedMH⁺=383. UV/MS(%)=100/96.

Example 1002-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-isopropylpiperidin-4-yl)acetamide(47AKU-7) 1-Trifluoroacetyl-4-piperidone (47AKU-2)

4-Piperidone hydrochloride monohydrate (3.85 g, 25 mmol) andTriethylamine (10.5 ml, 75 mmol) were partly dissolved in 100 ml ofdichloromethane and stirred for 10 min. Reaction mixture was then cooledon ice-bath and trifluoroacetic anhydride (7.2 ml, 50 mmol) was slowlyadded over 10 min. Ice-bath was removed and mixture was stirredovernight. Additional trifluoroacetic anhydride (2 ml) was added and themixture was stirred for 1 hr. Water (200ml) was added. Phases wereseparated and aq. phase was re-extracted with dichloromethane. Combinedorganic phases were washed with brine, dried over MgSO₄ and concentrated(40° C.) giving 4.97 g (100%) 47AKU-2 as yellow crystals. TLC (5%methanol in dichloromethane): R_(f)=0.8. ¹H-NMR (400 MHz, CDCl₃):δ=3.87-3.99 (4H, m); 2.54-2.61 (4H, m). ¹³C-NMR (CDCl₃): δ=204.7, 118.0,115.1, 44.2, 42.8, 41.2, 40.5.

4-(4-Methylbenzylamino)-1-trifluoroacetyl-piperidine (47AKU-3)

47AKU-2 (4.97 g, 25 mmol) was dissolved in 100 ml methanol and4-methylbenzyl-amine (3.2 ml, 25 mmol) was added. Mixture was stirredand acetic acid (˜2 ml) was added until pH˜5. NaCNBH₃ (3.15 g, 50 mmol)was slowly added. After magnetic stirring for 20 hrs the methanol waspartly removed on the rotary evaporator (40° C.). Dichloromethane, 2MNaOH and water were added until pH˜10. Phases were separated and aq.phase was then re-extracted twice with dichloromethane. Combined organicphases were washed with brine and dried over MgSO₄. Concentration(40°C.) yielded 6.94 g (92%) 47AKU-3. TLC (10% methanol in dichloromethane):R_(f)=0.6. HPLC-MS (Method A): M⁺=301.0 (UV/MS(%)=94/100).

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-trifluoroacetylpiperidin-4-yl)acetamide(47AKU4)

47AKU-3 (3.01 g, 10 mmol) in 25 ml of dichloromethane was placed in a100 ml flask. Triethylamine (1.4 ml, 10 mmol) was added and the mixturewas cooled on an ice-bath and stirred for 10 min. 4-Chlorophenylacetylchloride (1.90 g, 10 mmol) was dissolved in 10 ml dichloromethane andadded slowly to the ice-cold mixture. After 15 min. the ice-bath wasremoved and the mixture was left for 1 hr. Precipitation was observed.The reaction mixture was then concentrated at aspirator pressure(40°C.). The crude product was purified by flash chromatography (0-50%ethylacetate in heptane) yielding 2.38 g (53%) 47AKU4. TLC (100%dichloromethane): R_(f)=0.6. HPLC-MS (Method A): M⁺=453.0(UV/MS(%)=89/84).

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(piperidin-4-yl)acetamide(47AKU-6)

47AKU4 (2.38 g; ˜5 mmol) was dissolved in 50 ml of methanol. K₂CO₃ (3.5g; 25 mmol) was added in one portion. After magnetic stirring for 20hrs, additional K₂CO₃ (1 g) was added. After 4 hrs magnetic stirringmethanol was partly removed by evaporation(40° C.). Ethyl acetate (100ml) and water (100 ml) were added. The phases were separated and the aq.phase was then re-extracted with ethylacetate. The combined organicphases were dried over MgSO₄ and concentrated (40° C.) giving 1.95 g(100%) 47AKU-6. TLC (20% methanol in dichloromethane): R_(f)=0.3.HPLC-MS (Method A): M⁺=357.1 (UV/MS(%)=84/95).

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-isopropylpiperidin-4-yl)-acetamide(47AKU-7)

47AKU-6 (358 mg, 1.0 mmol) was dissolved in 20 ml of acetonitrile.Triethylamine (1.4 ml, 10 mmol) was added and mixture was stirred for 10min. Isopropyl bromide (370 mg, 3.0 mmol) was dissolved in 5 ml ofacetonitrile and added to the reaction mixturewhich was stirred at roomtemp. for 20 hrs and then heated to 60° C. for 4 hrs. After cooling,ethylacetate (25 ml) and water (25 ml) were added. The phases wereseparated and the aq. phase was then re-extracted with ethylacetate. Thecombined organic phases were washed with brine, dried over MgSO₄ andconcentrated(40° C.) giving 362 mg of crude product. Purification byflash chromatography (0-10% methanol in dichloromethane) andHCl-precipitation from 2M HCl/diethyl ether in dichloromethane/heptanegave 76 mg (18%) 47AKU-7. TLC (10% methanol in dichloromethane):R_(f)=0.4. Mp=223-224° C. HPLC-MS (Method A): M⁺=399.1(UV/MS(%)=100/99). ¹H-NMR (400 MHz, CDCl₃): δ=7.03-7.29 (8H, m); 4.86(1H, m); 4.61 (2H, m); 3.58 (2H, m); 3.37 (3H, m); 2.82 (2H, m); 2.64(2H, m); 2.34 (3H, s); 1.80 (2H, m); 1.39 (6H, d). ¹³C-NMR (CDCl₃):δ=172.4, 137.4, 134.8, 133.3, 133.1, 130.4, 129.9, 129.0, 125.8, 58.0,49.5, 48.2, 46.6, 40.4, 26.0, 21.2, 17.0.

Example 1012-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperidin-4-yl)acetamide(47AKU-12)

47AKU-6 (358 mg, 1.0 mmol) was dissolved in 20 ml of acetonitrile.Triethylamine (1.4 ml, 10 mmol) was added and the mixture was stirredfor 10 min. Ethyl bromide (370 μl, 5.0 mmol) was added. The mixture wasthen heated to 50° C. and stirred overnight. After cooling, water (25ml) and ethylacetate (25 ml) were added. The phases were separated andthe aq. phase was re-extracted with ethylacetate. The combined organicphases were washed with brine and dried over MgSO₄. Evaporation(40° C.)yielded 406 mg of crude product. Purification by ion exchangechromatography (washout with 10% aq. NH₄OH (25%) in methanol) gave 166mg (43%) 47AKU-12. The HCl-salt was prepared from 2M HCl/diethylether indichloromethane/heptane. TLC (10% methanol in dichloromethane):R_(f)=0.5. HPLC-MS (Method A): M⁺=385.1 (UV/MS(%)=100/99). ¹H-NMR (400MHz, CDCl₃, rotamers): δ=7.02-7.34 (8H, m); 4.62 (1H, m); 4.46 and 4.53(2H, 2s); 3.81 (1H, s); 3.55 (2H, s); 2.92 (2H, m); 2.34 (3H, s); 2.29(1H, s); 1.98 (2H, m); 1.52-1.84 (4H, m); 1.03 (3H, t). ¹³C-NMR (CDCl₃):δ=171.7, 137.2, 135.4, 133.9, 132.8, 130.4, 129.7, 128.9, 125.8, 52.8,52.4, 46.5, 40.8, 31.2, 29.8, 21.2, 12.4.

Example 1022-Phenyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide(47AKU-13)

47AKU-5 (218mg, 1.0 mmol) was dissolved in 2 ml of dichloromethane in a50 ml flask. Phenylacetyl chloride (134 μl, 1.0 mmol) was added. After 3hrs stirring at room temp. mixture was concentrated on Rotavapor (40°C.). Crude product was purified by ion exchange chromatography (washoutwith 10% aq. NH₄OH (25%) in methanol) and flash chromatography (0-10%methanol in dichloromethane) giving 48 mg (14%) 47AKU-13. HCl-salt wasprepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10%methanol in dichloromethane): R_(f)=0.4. HPLC-MS (Method A): M⁺=337.1(UV/MS(%)=98/98). ¹H-NMR (400 MHz, CDCl₃, rotamers): δ=7.01-7.40 (9H,m); 4.63 (1H, m); 4.53 and 4.45 (2H, 2s); 3.85 and 3.61 (2H, 2s); 2.86and 2.77 (2H, 2m); 2.35 and 2.29 (3H, 2s); 2.25 and 2.20 (3H, 2s); 2.09(2H, m); 1.61-1.86 (4H, m). ¹³C-NMR (CDCl₃): δ=172.2, 137.1, 135.5,129.7, 128.9, 128.8, 127.2, 126.9, 125.8, 55.3, 51.6, 46.6, 46.1, 41.6,29.5, 21.2.

Example 1032-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide(47AKU-8)

4-(4-Methylbenzylamino)-1-methyl-piperidine (47AKU-5)1-Methyl-4-piperidone (1.13 g, 10 mmol) was dissolved in 20 ml ofmethanol and added to a 100 ml flask. 4-Methylbenzylamine (1.21 g, 10mmol) in 10 ml of methanol was added. Acetic acid (˜1.5 ml) was addeduntil pH˜5. NaCNBH₃ (1.26 g, 20 mmol) was slowly added. After 20 hrsmagnetic stirring methanol was partly removed on Rotavapor (40° C.).Dichloromethane, water and 2M NaOH were added until pH˜10. The phaseswere separated and aq. phase was extracted twice with dichloromethane.The combined organic phases were washed with brine and dried over MgSO₄.Concentration on Rotavapor (40° C.) yielded 2.06 g crude (93%) 47AKU-5.TLC (20% methanol in dichloromethane): R_(f)=0.3. HPLC-MS (Method A):M⁺=219.1 (UV/MS(%)=89/98).

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide

(47AKU-8)

47AKU-5 (437 mg, 2.0 mmol) was dissolved in 10 ml of dichloromethane ina 50 ml flask. Triethylamine (280 μl, 2.0 mmol) was added and themixture was cooled to 0° C. on an ice bath and stirred for 10 min.4-Chlorophenylacetyl chloride (380 mg, 2.0 mmol) was dissolved in 10 mlof dichloromethane and added to the cooled mixture. After 2 hrs stirringat room temp. additional dichloromethane (10 ml) and water (20 ml) wereadded. The phases were separated and the aq. phase was re-extracted withdichloromethane. The combined organic phases were dried over MgSO₄ andconcentrated on the Rotavapor (40° C.) giving 755 mg of crude product.Purification by flash chromatography (0-10% methanol in dichloromethane)gave 485 mg (65%) product. Further purification by ion exchangechromatography (washout with 10% aq. NH₄OH (25%) in methanol) gave 239mg (32%) 47AKU-8. The HCl-salt was prepared from 2M HCl/diethylether indichloromethane/heptane. TLC (10% methanol in dichloromethane):R_(f)=0.4. Mp=217-219° C. HPLC-MS (Method A): M⁺=371.1 (UV/MS(%)=99/99).¹H-NMR (400 MHz, CD₃OD): δ=7.05-7.39 (8H, m); 4.80 (3H, s); 4.62+4.56(2H, 2s); 4.35 (1H, m); 4.00 (1H, s); 3.71 (1H, s); 3.46 ( 2H, m); 3.06(2H, m); 2.80 (3H, s); 2.32+2.27 (3H, 2s); 2.19 (1H,m). ¹³C-NMR (CD₃OD):δ=173.0, 137.5, 134.5, 133.9, 132.6, 130.6, 129.5, 128.5, 126.2, 54.0,51.4, 42.6, 40.2, 31.8, 26.6, 19.9.

Example 1042-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclopentylpiperidin-4-yl)-acetamide(47AKU-11)

47AKU-6 (358 mg, 1,0 mmol) was dissolved in 20 ml of acetonitrile.Triethylamine (1.4 ml, 10 mmol) was added and mixture was stirred for 10min. Cyclopentylbromide (540 μl, 5.0 mmol) was added and the mixture wasstirred at room temp. After 20 hrs the mixture was heated to 50° C. foran additional 24 hrs. The reaction mixture was then cooled and water (25ml) and ethylacetate (25 ml) were added. The phases were separated andthe aq. phase was re-extracted with ethylacetate. The combined organicphases were washed with brine and dried over MgSO₄. Concentration onRotavapor (45° C.) yielded 426 mg of crude product. Purification by ionexchange chromatography (washout with 10% aq. NH₄OH (25%) in methanol)and flash chromatography (0-10% methanol in dichloromethane) gave 76 mg(18%) 47AKU-11. The HCl-salt was prepared from 2M HCl/diethylether indichloromethane/heptane. TLC (10% methanol in dichloromethane):R_(f)=0.5. HPLC-MS (Method A): M⁺=425.1 (UV/MS(%)=100/97). ¹H-NMR (400MHz, CDCl₃, rotamers): δ=7.01-7.34 (8H, m); 4.67 (1H, m); 4.49 and 4.52(2H, 2s); 3.54 (2H, s); 3.15 and 3.02 (2H, 2m); 2.64 (1H, m); 2.27 and2.34 (3H, 2s); 2.20 (1H, m); 1.85 (4H, m); 1.69 (4H, m); 1.53 (4H, m);1.37 (1H, m). ¹³C-NMR (CDCl₃): δ=171.9, 137.2, 135.2, 133.8, 132.9,130.4, 129.7, 128.9, 125.8, 67.7, 52.4, 52.1, 46.5, 40.7, 30.2, 28.8,24.3, 21.2.

Example 1052-(4-Flourophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide(47AKU-14)

47AKU-5 (218mg, 1.0 mmol) was dissolved in 3 ml of dichloromethane in a50 ml flask. 4-Fluorophenylacetyl chloride (150 μl, 1.1 mmol) was added.After 4 hrs stirring at room temp. the mixture was concentrated onRotavapor (40° C.). The crude product was purified by flashchromatography (0-10% methanol in dichloromethane) giving 243 mg (68%)47AKU-14. The HCl-salt was prepared from 2M HCl/diethylether indichloromethane/heptane. TLC (10% methanol in dichloromethane):R_(f)=0.5. HPLC-MS (Method A): M⁺=355.1 (UV/MS(%)=100/100). ¹H-NMR (400MHz, CDCl₃): δ=6.92-7.33 (8H, m); 4.73 (1H, m); 4.52 (2H, s); 3.56 (2H,2s); 3.44 (5H, m); 3.25 (2H, m); 2.52-2.67 (4H, m); 2.33 (3H, s).¹³C-NMR (CDCl₃): δ=172.5, 163.3, 160.9, 139.5, 134.8, 130.6, 129.8,125.8, 115.8, 54.6, 50.8, 49.9, 46.7, 40.4, 27.2, 21.2.

Example 1062-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-(2-hydroxyethyl)-piperidin-4-yl)-acetamide(47AKU-18)

47AKU-6-2 (358 mg, 1,0 mmol) was dissolved in 10 ml of acetonitrile in50 ml flask. Triethylamine (1.4 ml, 10 mmol) was added and mixture wasstirred for 10 min.

2-Bromoethanol (215 μl, 3.0 mmol) was added. Reaction mixture was thenheated to 60° C. and stirred overnight. After cooling ethylacetate (25ml) and water (25 ml) were added. Phases were separated and aq. phasewas re-extracted with ethylacetate. Combined organic phases were washedwith brine, dried over MgSO₄ and concentrated on Rotavapor (40° C.)giving 406 mg crude product. Purification by flash chromatography (0-10%methanol in dichloromethane) afforded 253 mg (63%) 47AKU-18. HCl-saltwas prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC(10% methanol in dichloromethane): R_(f)=0.4. HPLC-MS (Method A):M⁺=401.1 (UV/MS(%)=100/100). ¹H-NMR (400 MHz, CDCl₃, rotamers):δ=7.04-7.34 (8H, m); 4.60 (1H, m); 4.52 and 4.45 (2H, 2s); 3.55 (4H, m);3.03 (1H, bs); 2.92 (2H, m); 2.52 (2H, m); 2.36 and 2.31 (3H, 2s); 2.19(2H, m); 1.66 (4H, m).). ¹³C-NMR (CDCl₃): δ=171.7, 137.3, 135.2, 133.8,132.9, 130.4, 129.8, 128.9, 125.8, 59.4, 58.1, 53.1, 52.3, 46.8, 40.8,29.7, 21.2.

Example 1072-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-yl)-acetamide(47AKU-19) 1-Cyclobutyl4-piperidone (47AKU-15)

Partly dissolved quartenary salt (1.23 g, 3.7 mmol) (prepared accordingto the procedure outlined in the synthesis of 47AKU47) was slowly addedto a refluxing solution of Cyclobutylamine (178 mg, 2.5 mmol) andPotassium carbonate (48 mg, 0.34 mmol) in ethanol. The mixture wasrefluxed for 1.5 hrs. After cooling to room temp. water (10 ml) anddichloromethane (25 ml) were added. Phases were separated and aq. phasewas re-extracted with dichloromethane. Combined organic phases weredried over MgSO₄ and concentrated on Rotavapor (40° C.) giving 419 mgcrude 47AKU-15. TLC (10% methanol in dichloromethane): R_(f)=0.4.HPLC-MS (Method A): M⁺=154.1 (MS(%)=75).

4-(4-Methylbenzylamino)-1-cyclobutyl-piperidine (47AKU-16)

4-Methylbenzylamine (215 mg, 1.8 mmol) was dissolved in 5 ml methanoland placed in 50 ml flask. 47AKU-15 (270 mg, 1.8 mmol) in 5 ml methanolwas added. Acetic acid (0.3 ml) was added until pH˜5. NaCNBH₃ (226 mg,3.6 mmol) was slowly added. Gas evolution observed. After 24 hrsmagnetic stirring dichloromethane, 2M NaOH and water were added untilpH˜10. Phases were separated and aq. phase was then re-extracted withdichloromethane. Combined organic phases were dried over MgSO₄ andconcentrated on Rotavapor (40° C.) yielding 419 mg crude 47AKU-16. TLC(10% methanol in dichloromethane): R_(f)=0.3. HPLC-MS (Method A):M⁺=259.1 (UV/MS(%)=44/87).

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-yl)-acetamide(47AKU-19)

47AKU-16 (209 mg, 0.8 mmol) was placed in. 50 ml flask and 5 mldichloromethane was added. 4-Chlorophenylacetyl chloride (171 mg, 0.9mmol) in 5 ml dichloromethane was added. After 5 hrs magnetic stirringthe reaction mixture was concentrated on Rotavapor (40° C.). Crudeproduct was purified by flash chromatography (0-10% methanol indichloromethane) giving 101 mg (31%) product. Further purification byion exchange chromatography (washout with 10% aq. NH₄OH (25%) inmethanol) gave 55 mg (17%) 47AKU-19. Oxalate-salt was prepared fromOxalic acid (1.1 eq) in dichloromethane/ heptane. TLC (10% methanol indichloromethane): R_(f)=0.6. HPLC-MS (Method B): M⁺=411.2(UV/MS(%)=91/86). ¹H-NMR (400 MHz, CDCl₃, rotamers): δ=7.33-7.01 (8H,m); 4.62 (1H, m); 4.52 and 4.46 (2H, 2s); 3.80 (1H, s); 3.45 and 3.54(2H, 2s); 2.86 (2H, m); 2.66 (2H, m); 2.28 and 2.34 (3H, 2s); 1.98 (2H,m); 1.80 (2H, m); 1.70-1.52 (6H,m). ¹³C-NMR (CDCl₃): δ=171.7, 137.2,135.4, 133.9, 132.9, 130.4, 129.7, 128.9, 125.7, 60.4, 52.3, 49.4, 46.5,40.7, 29.4, 27.6, 21.2, 14.2.

Example 1082-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-yl)acetamide(47AKU-20)

47AKU-16 (209 mg, 0.8 mmol) was placed in 50 ml flask and 5 mldichloromethane was added. 4-Methoxyphenylacetyl chloride (167 mg, 0.9mmol) in 5 ml dichloromethane was added. After 5 hrs magnetic stirringthe reaction mixture was concentrated on Rotavapor (40° C.). Crudeproduct was purified by flash chromatography (0-10% methanol indichloromethane) giving 72 mg (22%) product. Further purification by ionexchange chromatography (washout with 10% aq. NH₄OH (25%) in methanol)gave 67 mg (20%) 47AKU-20. Oxalate-salt was prepared from Oxalic acid(1.1 eq) in dichloromethane/heptane. TLC (10% methanol indichloromethane): R^(f)=0.6. HPLC-MS (Method B): M⁺=407.3(UV/MS(%)=93/77). ¹H-NMR (400 MHz, CDCl₃, rotamers): δ 7.26-6.79 (8H,m); 4.62 (1H, m); 4.52 and 4.45 (2H, 2s); 3.79 (1H, m); 3.77 (3H, s);3.52 and 3.45 (2H, 2s); 2.84 (2H, m); 2.66 (2H, m); 2.34 and 2.28 (3H,2s); 1.98 (2H, m); 1.81 (2H, m); 1.72-1.51 (6H,m). ¹³C-NMR(CDCl₃): δ172.5, 158.7, 137.0, 135.7, 130.4, 129.8, 127.4, 125.8, 114.3, 60.4,55.5, 52.1, 49.4, 46.4, 40.6, 29.4, 27.6, 21.2, 14.2.

Example 109 (47AKU-21)2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide(47AKU-21) 4-(4-Methylbenzylamino)-tropane (47AKU-17)

4-Methylbenzylamine (607 mg, 5.0 mmol) was dissolved in 10 ml methanoland placed in 100 ml flask. Tropinone (697 mg, 5.0 mmol) in 10 mlmethanol was added. Acetic acid (0.75 ml) was added until pH˜5. NaCNBH₃(628 mg, 10 mmol) was slowly added. Gas evolution observed. After 20 hrsmagnetic stirring dichloromethane, 2M NaOH and water were added untilpH˜10. Phases were separated and aq. phase was then re-extracted withdichloromethane. Combined organic phases were dried over MgSO₄.Concentration on Rotavapor (40° C.) yielded 1.14 g crude 47AKU-17. TLC(10% methanol in dichloromethane): R^(f)=0.4. HPLC-MS (Method A):M⁺=245.2 (UV/MS(%)=65/96).

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide (47AKU-21)

47AKU-17 (244 mg, 1.0 mmol) was placed in 50 ml flask and 5 mldichloromethane was added. 4-Methoxyphenylacetyl chloride (203 mg, 1.1mmol) in 10 ml dichloromethane was added. After 3 hrs magnetic stirringthe reaction mixture was concentrated on Rotavapor (40° C.). Crudeproduct was purified by ion exchange chromatography (washout with 10%aq. NH₄OH (25%) in methanol) and flash chromatography (0-10% methanol indichloromethane) giving 202 mg (51%) 47AKU-21. Oxalate-salt was preparedfrom Oxalic acid (1.1 eq) in dichloromethane/heptane. TLC (10% methanolin dichloromethane): R^(f) 0.4. HPLC-MS (Method B): M⁺=393.3(UV/MS(%)=94/92). ¹H-NMR (400 MHz, CDCl₃, isomers): δ 7.02-7.17 (6H, m);6.78-6.87 (2H, m); 4.74 (1H, s); 4.44 (1H, s); 3.78 and3.77 (3H, 2s);3.68 (1H, m); 3.66 and 3.55 (3H, 2s); 2.65 (2H, m); 2.56 (2H, m); 2.32(3H, s); 2.12-2.26 (6H, m); 2.05 (2H, m). ¹³C-NMR (CDCl₃): δ 173.2,171.4, 158.8, 137.1, 129.7, 127.6, 126.9, 126.0, 114.4, 63.4, 60.9,55.5, 54.6, 47.5, 41.5, 40.4, 32.8, 31.1, 27.5, 24.9, 21.2.

Example 110N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′-benzyl-carbamide(47AKU-22)

47AKU-5 (219 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane andplaced in 50 ml flask. Benzylisocyanate (160 mg, 1.2 mmol) in 5 mldichloromethane was added. After 16 hrs magnetic stirring the reactionmixture was concentrated on Rotavapor (40° C.). Crude product waspurified by flash chromatography (0-10% methanol in dichloromethane)giving 236 mg (67%) 47AKU-22. Oxalate-salt was prepared from Oxalic acid(1.1 eq) in dichloromethane/heptane. TLC (10% methanol indichloromethane): R_(f)=0.5. HPLC-MS (Method B): M⁺=352.3(UV/MS(%)=100/100). ¹H-NMR (400 MHz, CDCl₃): δ=7.26-7.02 (9H, m); 4.61(1H, m); 4.41 (1H, m); 4.33 (4H, m); 2.87 (2H, m); 2.32 (3H, s); 2.25(3H, s); 2.09 (2H, m); 1.79-1.62 (4H, m). ¹³C-NMR (CDCl₃): δ=158.6,139.7, 137.3, 135.4, 129.8, 128.6, 127.4, 127.2, 126.2, 55.5, 52.2,46.2, 45.8, 45.0, 30.2, 21.2.

Example 111 N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′-phenylcarbamide (47AKU-24)

47AKU-5 (219 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane andplaced in 50 ml flask. Phenylisocyanate (143 mg, 1.2 mmol) in 5 mldichloromethane was added. After 4 hrs magnetic stirring the reactionmixture was concentrated on Rotavapor (40° C.). Crude product waspurified by flash chromatography (0-10% methanol in dichloromethane)giving 181 mg (54%) 47AKU-24. HCl-salt was prepared from 2MHCl/diethylether in dichloromethane/heptane. TLC (10% methanol indichloromethane): R_(f)=0.4. HPLC-MS (Method A): M⁺=338.3(UV/MS(%)=100/100). ¹H-NMR (400 MHz, CDCl₃): δ=7.12-7.24 (8H, m);6.93-6.98 (1H, m); 6.26 (1H, s); 4.45 (3H, s); 2.90 (2H, d); 2.36 (3H,s); 2.28 (3H, s); 2.12 (2H, m); 1.69-1.85 (4H, m). ¹³C-NMR (CDCl₃):δ=156.1, 139.3, 137.8, 134.9, 130.1, 128.9, 126.3, 123.1, 119.9, 55.5,52.3, 46.3, 46.2, 30.3, 21.3.

Example 112 N-Phenethyl-N-(1-methylpiperidin-4-yl)-N′-benzyl-carbamide(47AKU-25)

4-(2-Phenylethyl)amino-1-methylpiperidine (110 mg, 0.5 mmol) wasdissolved in 5 ml dichloromethane and placed in 50 ml flask.Benzylisocyanate (80 mg, 0.6 mmol) in 5 ml dichloromethane was added.After 20 hrs magnetic stirring the reaction mixture was concentrated onRotavapor (40° C.). Crude product was purified by flash chromatography(0-10% methanol in dichloromethane) giving 164 mg (84%) 47AKU-25.HCl-salt was prepared from 2M HCl/diethylether indichloromethane/heptane. TLC (10% methanol in dichloromethane):R_(f)=0.4. HPLC-MS (Method A): M⁺=352.3 (UV/MS(%)=100/100). ¹H-NMR (400MHz, CDCl₃): δ=7.34-7.09 (10H, m); 4.52 (1H, m); 4.35 (2H, d); 4.08 (1H,m); 3.33 (2H, t); 2.92 (2H); m); 2.82 (2H, t); 2.28 (3H, s); 2.07 (2H,m); 1.84-1.66 (4H, m). ¹³C-NMR (CDCl₃): δ=157.9, 139.8, 139.1, 129.0,128.9, 128.8, 127.8, 127.4, 126.9, 55.7, 52.8, 46.2, 45.3, 44.8, 37.5,30.6.

Example 1132-Phenyl-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide(47AKU-26a)

50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane in 50ml flask.

4-Fluorophenylacetyl chloride (104 mg, 0.6 mmol) was added. After 20 hrsstirring at room temp. mixture was concentrated on Rotavapor (40° C.).Crude product was purified by flash chromatography (0-10% methanol indichloromethane) giving 87 mg (49%) 47AKU-26a. HCl-salt was preparedfrom 2M HCl/diethylether in dichloromethane/heptane. HPLC-MS (Method A):M⁺=353.1 (UV/MS(%)=96/88).

Example 1142-(4-Trifluoromethylphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide(47AKU-26b)

50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane in 50ml flask.

4-Trifluoromethylphenylacetyl chloride (134 mg, 0.6 mmol) was added.After 20 hrs stirring at room temp. mixture was concentrated onRotavapor (40° C.). Crude product was purified by flash chromatography(0-10% methanol in dichloromethane) giving 81 mg (39%) 47AKU-26b.HCl-salt was prepared from 2M HCl/diethylether indichloromethane/heptane. HPLC-MS (Method A): M⁺=421.1 (UV/MS(%)=90/100).

Example 1152-(4-Fluorophenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide(47AKU-26c)

50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane in 50ml flask.

4-Fluorophenylacetyl chloride (104 mg, 0.6 mmol) was added. After 20 hrsstirring at room temp. mixture was concentrated on Rotavapor (40° C.).Crude product was purified by flash chromatography (0-10% methanol indichloromethane) giving 68 mg (37%) 47AKU-26c. HCl-salt was preparedfrom 2M HCl/diethylether in dichloromethane/heptane. HPLC-MS (Method A):M⁺=371.1 (UV/MS(%)=100/97).

Example 1162-(4-Methoxyphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide(47AKU-26d)

50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane in 50ml flask.

4-Methoxyphenylacetyl chloride (111 mg, 0.6 mmol) was added. After 20hrs stirring at room temp. mixture was concentrated on Rotavapor (40°C.). Crude product was purified by flash chromatography (0-10% methanolin dichloromethane) giving 77 mg (40%) 47AKU-26d. HCl-salt was preparedfrom 2M HCl/diethylether in dichloromethane/heptane. HPLC-MS (Method A):M⁺=383.1 (UV/MS(%)=100/100).

Example 1172-(4-Methylphenyl)-N-(4-chlorobenzyl)-N-(1-methylpiperidin-4-yl)-acetamide(47AKU-28) 4-(4-Chlorobenzylamino)-1-methyl-piperidine (47AKU-27)

1-Methyl-4-piperidone (566 mg, 5.0 mmol) was dissolved in 10 ml methanoland placed in 100 ml flask. 4-Chlorobenzylamine (708 mg, 5.0 mmol) wasadded. Mixture was stirred and Acetic acid (˜0.75 ml) was added untilpH˜5. NaCNBH₃ (628 mg, 10 mmol) was slowly added. Gas evolutionobserved. After magnetic stirring for 16 hrs methanol was partly removedon Rotavapor (40° C.). Dichloromethane, 2M NaOH and water were addeduntil pH˜10. Phases were separated and aq. phase was then re-extractedwith dichloromethane. Combined organic phases were dried over MgSO₄.Concentration on Rotavapor (40° C.) yielded 1.14 g crude 47AKU-27. TLC(10% methanol in dichloromethane): R_(f)=0.3. HPLC-MS (Method A):M⁺=239.1 (MS(%)=96).

2-(4-Methylphenyl)-N-(4-chlorobenzyl)-N-(1-Methylpiperidin-4-yl)-acetamide

(47AKU-28)

p-Tolylacetic acid (1.50 g) was dissolved in 10 ml thionylchloride andplaced in 50 ml flask. Mixture was heated to reflux for 2 hrs and thenconcentrated on Rotavapor (40° C.).

p-Tolylacetic chloride (202 mg, 1.2 mmol) in 5 ml dichloromethane wasadded to 47AKU-27 (239 mg, 1.0 mmol) in 5 ml dichloromethane. After 4hrs magnetic stirring the reaction mixture was concentrated on Rotavapor(40° C.). Crude product was purified by flash chromatography (0-10%methanol in dichloromethane) giving 104 mg (28%) 47AKU-28. HCl-salt wasprepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10%methanol in dichloromethane): R_(f)=0.5. HPLC-MS (Method A): M⁺=371.1(UV/MS(%)=100/90). ¹H-NMR (400 MHz, CDCl₃, rotamers): δ=7.34-6.99 (8H,m); 4.57 (1H, m); 4.50 and 4.44 (2H, 2s); 3.80 (1H, s); 3.55 (1H, s);2.96 and 2.82 (2H, 2m); 2.34 (1H, m); 2.32 (3H, s); 2.24 and 2.15 (3H,2s); 1.91 (1H, m); 1.81-1.59 (4H,m). ¹³C-NMR (CDCl₃): δ=172.5, 138.2,136.8, 133.4, 131.8, 129.7, 129.2, 128.6, 127.4, 54.9, 51.3, 46.7, 41.3,30.6, 28.6, 21.2.

Example 1182-(4-Hydroxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide(47AKU-29)

42ELH-77 (41 mg, 0.1 mmol) was dissolved in 1 ml dry dichloromethane andplaced in oven-dried 10 ml flask. Mixture was cooled to −78° C. on adry-ice/isopropanol bath. Borontribromide (1.0 M in dichloromethane, 150μl, 0.15 mmol) was slowly added at −78° C. Ice-bath was removed andmixture was left at room temp. for 2 hrs. Water (3 ml) and saturatedNaCl (aq.) were added and aq. phase was extracted with dichloromethane,ethylacetate and n-butanol. Combined organic phases were dried overMgSO₄ and concentrated on Rotavapor (40° C.). Crude product was purifiedby flash chromatography (0-20% methanol in dichloromethane) giving 22 mg(63%) 47AKU-29. HCl-salt was prepared from 2M HCl/diethylether indichloromethane/heptane. TLC (10% methanol in dichloromethane):R_(f)=0.3. HPLC-MS (Method A): M⁺=353.2 (UV/MS(%)=100/100). ¹H-NMR (400MHz, CDCl₃, rotamers): δ=7.07-6.60 (8H, m); 4.48 (1H, m); 4.39 (2H, s);3.76 and 3.66 (4H, 2bs); 3.41 (2H, s); 3.08 (2H,m); 2.49 (1H, m); 2.42(2H, bs); 2.22 and 2.16 (3H, 2s); 1.96-1.82 (2H, m); 1.66-1.56 (1H,m).¹³C-NMR (CDCl₃): δ=173.7, 156.0, 137.3, 134.6, 129.7, 129.6, 125.7,125.4, 115.7, 54.4, 50.4, 46.8, 44.0, 40.5, 27.3, 20.9.

Example 119 N-Phenethyl-N-(1-methylpiperidin-4-yl)-N′-phenyl-carbamide(47AKU-30)

4-(2-Phenylethyl)amino-1-methylpiperidine (110 mg, 0.5 mmol) wasdissolved in 5 ml dichloromethane and placed in 50 ml flask.Phenylisocyanate (71 mg, 0.6 mmol) in 5 ml dichloromethane was added.After 16 hrs magnetic stirring the reaction mixture was concentrated onRotavapor (40° C.). Crude product was purified twice by flashchromatography (0-10% methanol in dichloromethane) giving 131 mg (78%)47AKU-30. HCl-salt was prepared from 2M HCl/diethylether indichloromethane/heptane. TLC (10% methanol in dichloromethane):R_(f)=0.4. HPLC-MS (Method A): M⁺=338.1 (UV/MS(%)=99/100). ¹H-NMR (400MHz, CDCl₃): δ=7.36-6.93 (10H, m); 6.24 (1H, s); 4.31 (1H, m); 3.50 (2H,t); 3.20 (2H, d); 2.89 (2H, t); 2.57 (2H, m); 2.50 (3H, s); 2.26 (2H,m); 1.79 (2H, m). ¹³C-NMR (CDCl₃): δ=155.8, 139.2, 139.0, 129.4, 129.3,128.9, 127.3, 123.2, 120.4, 54.9, 51.3, 45.5, 44.3, 37.6, 28.3.

Example 120N-(3-Phenylpropyl)-N-(1-methylpiperidin-4-yl)-N′-benzyl-carbamide(47AKU-31)

4-(3-Phenylpropyl)amino-1-methylpiperidine(160 mg, 0.7 mmol) wasdissolved in 5 ml dichloromethane and placed in 50 ml flask.Benzylisocyanate (107 mg, 0.8 mmol) in 5 ml dichloromethane was added.After 2 hrs magnetic stirring the reaction mixture was concentrated onRotavapor (40° C.). Crude product was purified twice by flashchromatography (0-10% methanol in dichloromethane) giving 156 mg (61%)47AKU-31. HCl-salt was prepared from 2M HCl/diethylether indichloromethane/heptane. TLC (10% methanol in dichloromethane):R_(f)=0.3. HPLC-MS (Method A): M⁺=366.1 (UV/MS(%)=100/100). ¹H-NMR (400MHz, CDCl₃): δ=7.34-7.07 (10H, m); 4.33 (3H, m); 4.14 (1H, m); 3.04 (2H,m); 2.89 (2H, d); 2.57 (2H, t); 2.28 (3H, s); 2.06 (2H, m); 1.87 (2H,m); 1.75-1.62 (4H, m). ¹³C-NMR (CDCl₃): δ=157.5, 141.0, 140.0, 129.0,128.6, 128.3, 128.0, 127.6, 126.6, 55.6, 52.1, 46.3, 45.1, 41.6, 33.4,32.2, 30.6.

Example 121N-(3-Phenylpropyl)-N-(1-methylpiperidin-4-yl)-N-phenyl-carbamide(47AKU-32)

4-(3-Phenylpropyl)amino-1-methylpiperidine (160 mg, 0.7 mmol) wasdissolved in 5 ml dichloromethane and placed in 50 ml flask.Phenylisocyanate (95 mg, 0.8 mmol) in 5 ml dichloromethane was added.After 20 hrs magnetic stirring the reaction mixture was concentrated onRotavapor (40° C.). Crude product was purified by flash chromatography(0-10% methanol in dichloromethane) giving 106 mg (43%) 47AKU-32.HCl-salt was prepared from 2M HCl/diethylether indichloromethane/heptane. TLC (10% methanol in dichloromethane):R_(f)=0.3. HPLC-MS (Method A): M⁺=352.1 (UV/MS(%)=100/100). ¹H-NMR (400MHz, CDCl₃): δ=7.35-6.95 (10H, m); 5.99 (1H, s); 4.18 (1H, m); 3.17 (2H,t); 2.91 (2H, d); 2.65 (2H, t); 2.28 (3H, s); 2.07 (2H, m); 1.97 (2H,m); 1.81-1.66 (4H, m). ¹³C-NMR (CDCl₃): δ=154.9, 141.0, 139.3, 129.2,129.0, 129.0, 126.8, 123.1, 120.0, 55.6, 52.2, 46.2, 41.8, 33.4, 32.3,30.6.

Example 1222-(4-Methoxyphenyl)-2,2-ethylene-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(47AKU-33)

1-(4-Methoxyphenyl)-1-cyclopropane carboxylic acid (230 mg, 1.2 mmol)was dissolved in 2 ml thionylchloride and placed in 50 ml flask. Mixturewas heated to reflux for 2 hrs and then concentrated on Rotavapor (40°C.). The acid chloride (250 mg, 1.2 mmol) in 5 ml dichloromethane wasadded to 47AKU-5 (220 mg, 1.0 mmol) in 5 ml dichloromethane. After 2 hrsmagnetic stirring the reaction mixture was concentrated on Rotavapor(40° C.). Crude product was purified twice by flash chromatography(0-10% methanol in dichloromethane) giving 201 mg (51%) 47AKU-33.HCl-salt was prepared from 2M HCl/diethylether indichloromethane/heptane. TLC (10% methanol in dichloromethane):R_(f)=0.6. HPLC-MS (Method A): M⁺=393.2 (UV/MS(%)=95/88).

¹H-NMR (400 MHz, CDCl₃, rotamers): δ=7.22-6.70 (8H, m); 4.44 (2H, s);4.26 (1H, m); 3.74 (3H, s); 3.12 and 2.89 (2H, 2m); 2.51 (1H, m); 2.32(3H, m); 2.26 (3H, s); 2.08-1.52 (4H, m); 1.36 (2H, bs); 1.15-0.95 (3H,m). ¹³C-NMR (CDCl₃): δ=172.9, 158.6, 136.6, 132.7, 129.2, 128.6, 127.9,127.4, 114.4, 55.5, 55.1, 54.4, 45.2, 45.0, 29.8, 29.2, 21.2, 13.8.

Example 1232-(4-Methoxyphenyl)-N-(1-phenylethyl)-N-(1-methylpiperidin-4-yl)acetamide(47AKU-37) 4-Alpha-methylbenzylamino-1-methyl-piperidine (47AKU-36)

DL-Phenylethylamine (606 mg, 5.0 mmol) was dissolved in 10 ml methanoland 1-Methyl-4-piperidone (566 mg, 5.0 mmol) in 1.0 ml methanol wasadded. Mixture was stirred and Acetic acid (˜0.75 ml) was added untilpH˜5. NaCNBH₃ (628 g, 10 mmol) was slowly added. Gas evolution observed.After magnetic stirring for 20 hrs methanol was partly removed onRotavapor (40° C.). Ethylacetate, 2M NaOH and water were added untilpH˜10. Phases were separated and aq. phase was then re-extracted withethylacetate and dichloromethane. Combined organic phases were driedover MgSO₄. Concentration on Rotavapor (40° C.) yielded 838 mg crude47AKU-36. TLC (10% methanol in dichloromethane): R_(f)=0.3. HPLC-MS(Method A): M⁺=219.1 (UV/MS(%)=100/94).

2-(4-Methoxyphenyl)-N-alpha-methylbenzyl-N-(1-methylpiperidin-4-yl)acetamide(47AKU-37)

47AKU-36 (218 mg, 1.0 mmol) was dissolved in 10 ml dichloromethane andplaced in 50 ml flask. 4-Methoxyphenylacetyl chloride (185 mg, 1.2 mmol)in 10 ml dichloromethane was added. After 16 hrs magnetic stirring thereaction mixture was concentrated on Rotavapor (40° C.). Crude productwas purified by flash chromatography (0-10% methanol in dichloromethane)giving 256 mg (70%) 47AKU-37. HCl-salt was prepared from 2MHCl/diethylether in dichloromethane/heptane. TLC (10% methanol indichloromethane): R^(f)=0.5. HPLC-MS (Method A): M⁺=367.3(UV/MS(%)=100/99).

¹H-NMR (400 MHz, CDCl₃, rotamers): δ 7.34-7.06 (7H, m); 6.84 (2H, d);5.10 (1H, m); 3.77 (3H, s); 3.67 (2H, m); 3.17 (1H, m); 3.03-2.75 (3H,m); 2.64 (3H, s); 2.38 (2H, m); 1.77-1.05 (6H, m). ¹³C-NMR (CDCl₃): δ172.0, 158.9, 139.9, 130.0, 129.0, 128.2, 127.1, 114.5, 55.5, 53.1,51.4, 42.4,41.3, 31.1, 29.5, 24.9, 18.1.

Example 1242-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-aza-bicyclo[3.2.1]octen-3-yl)-acetamide(47AKU-39) 4-Methylbenzylimino-tropane (47AKU-38)

4-Methylbenzylamine (1.21 g, 10 mmol) and Tropinone (1.39 g, 10 mmol)were placed in 100 ml flask and dissolved in 50 ml toluene. Mixture washeated to reflux for 3 hrs and water was removed using a Dean/Starkwater separator. Crude product was concentrated on Rotavapor (40° C.)giving 47AKU-38. TLC (10% methanol in dichloromethane): R^(f)=0.3.¹H-NMR (400 MHz, CDCl₃, isomers): 7.20-7.09 (4H, m); 4.47 (1H, m); 3.81(1H, s); 3.42 (1H, m); 3.31 (1H, m); 2.77-2.56 (2H, m); 2.47 and 2.41(3H, 2s); 2.33 and 2.31 (3H, 2s); 2.27-1.97 (4H, m); 1.69-1.54 (2H, m).

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(3-tropen-4-yl)acetamide(47AKU-39)

47AKU-38 (242 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane andplaced in 50 ml flask. 4-Methoxyphenylacetyl chloride (185 mg, 1.2 mmol)in 10 ml dichloromethane was added. After 16 hrs magnetic stirring thereaction mixture was concentrated on Rotavapor (40° C.). Crude productwas purified by flash chromatography (0-10% methanol in dichloromethane)giving 69 mg (18%) 47AKU-39. HCl-salt was prepared from 2MHCl/diethylether in dichloromethane/heptane. TLC (10% methanol indichloromethane): R_(f)=0.4. HPLC-MS (Method A): M⁺=391.2(UV/MS(%)=91/86).

¹H-NMR (400 MHz, CDCl₃, rotamers): δ=7.22-6.82 (8H, m); 5.41 (1H, bs);4.71-4.52 (2H, m); 3.78 (3H, s); 3.68 (2H, m); 3.44-3.24 (2H, m);2.72-2.36 (5H, m); 2.32 (3H, s); 2.25-2.00 (2H, m); 1.80-1.54 (2H, m).¹³C-NMR (CDCl₃): δ=170.8, 158.7, 137.4, 134.9, 130.1, 129.3, 128.9,126.9, 114.2, 59.0, 58.0, 55.5, 49.5, 46.3, 39.7, 35.9, 33.8, 29.7,21.3.

Example 1252-Phenyl-2-ethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(47AU-40)

2-Phenylbutyric acid (197 mg, 1.2 mmol) was dissolved in 2 mlthionylchloride and placed in 50 ml flask. Mixture was heated to refluxfor 2 hrs and then concentrated on Rotavapor (50° C.). The acid chloride(1.2 mmol) in 5 ml dichloromethane was added to 47AKU-5 (158 mg, 0.72mmol) in 5 ml dichloromethane. After 20 hrs magnetic stirring thereaction mixture was concentrated on Rotavapor (40° C.). Crude productwas purified by flash chromatography (0-10% methanol in dichloromethane)giving 196 mg (74%) 47AKU40. HCl-salt was prepared from 2MHCl/diethylether in dichloromethane/heptane. TLC (10% methanol indichloromethane): R_(f)=0.5. HPLC-MS (Method A): M⁺=365.4(UV/MS(%)=99/100). ¹H-NMR (400 MHz, CDCl₃, rotamers): δ=7.32-6.98 (8H,m); 4.77 (1H, bs); 4.50 (1H, d); 4.29 (1H, d); 3.43 and 3.21 (3H, 2m);2.72 (2H, m); 2.62 (3H, s); 2.43 (1H, m); 2.32 (3H, s); 2.21 (3H, m);2.04 (2H, m); 1.67 (3H, m); 0.92-0.72 (3H, m). ¹³C-NMR (CDCl₃): δ=174.7,139.9, 137.3, 135.2, 129.7, 129.0, 127.8, 127.3, 125.8, 54.5, 51.6,49.4, 46.0, 43.8, 28.9, 26.7, 26.3, 21.2, 12.7.

Example 1262-(4-Methoxyphenyl)-N-(1-indanyl)-N-(1-methylpiperidin-4-yl)acetamide(47AKU43) 4-(1-Indanamino)-1-methyl-piperidine (47AKU42)

1-Aminoindane (666 mg, 5.0 mmol) was dissolved in 10 ml methanol andplaced in 100 ml flask. 1-Methyl-4-piperidone (566 mg, 5.0 mmol) in 10ml methanol was added. Mixture was stirred and Acetic acid (˜0.75 ml)was added until pH˜5. NaCNBH₃ (628 g, 10 mmol) was slowly added. Gasevolution observed. After magnetic stirring for 16 hrs methanol waspartly removed on Rotavapor (40° C.). Dichloromethane, 2M NaOH and waterwere added until pH˜10. Phases were separated and aq. phase was thenre-extracted with ethylacetate and dichloromethane. Combined organicphases were dried over MgSO₄. Concentration on Rotavapor (40° C.)yielded 1.06 g 47AK-U42. TLC (10% methanol in dichloromethane):R_(f)=0.3. HPLC-MS (Method A): M⁺=231.1 (UV/MS(%)=72/91).

2-(4-Methoxyphenyl)-N-(1-indanyl)-N-(1-methylpiperidin-4-yl)acetamide(47AKU-43)

47AKU42 (230 mg, 1.0 mmol) was dissolved in 10 ml dichloromethane andplaced in 50 ml flask. 4-Methoxyphenylacetyl chloride (185 mg, 1.2 mmol)in 10 ml dichloromethane was added. After 16 hrs magnetic stirring thereaction mixture was concentrated on Rotavapor (40° C.). Crude productwas purified by flash chromatography (0-10% methanol in dichloromethane)giving 194 mg (51%) 47AKU43. HCl-salt was prepared from 2MHCl/diethylether in dichloromethane/heptane. TLC (10% methanol indichloromethane): R_(f)=0.5. HPLC-MS (Method A): M⁺=379.2(UV/MS(%)=94/90).

Example 127(47AKU44)-N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-methoxybenzyl)-carbamide(47AKU44)

47AKU-5 (219 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane andplaced in 50 ml flask. 4-Methoxybenzylisocyanate (196 mg, 1.2 mmol) in10 ml dichloromethane was added. After 16 hrs magnetic stirring thereaction mixture was concentrated on Rotavapor (40° C.). Crude productwas purified by flash chromatography (0-10% methanol in dichloromethane)giving 192 mg (50%) 47AKU44. HCl-salt was prepared from 2MHCl/diethylether in dichloromethane/heptane. TLC (10% methanol indichloromethane): R_(f)=0.3. HPLC-MS (Method A): M⁺=382.3(UV/MS(%)=100/94). ¹H-NMR (400 MHz, CDCl₃): δ=7.10 (4H, m); 6.98 (2H,m); 6.76 (2H, m); 4.58 (1H, t); 4.45 (1H, m); 4.33 (2H, s); 4.25 (2H,d); 3.76 (3H, s); 2.97 (2H, m); 2.34 (3H, s); 2.32 (3H, s); 2.24 (2H,m); 1.78 (4H, m). ¹³C-NMR (CDCl₃): δ=158.9, 158.5, 137.3, 135.2, 131.8,129.8, 128.8, 126.2, 114.1, 55.5, 55.4, 51.7, 45.8, 45.7, 44.5, 29.7,21.2.

Example 1282-(3,4-dimethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(47AKU45)

3,4-Dimethoxyphenylbutyric acid (235 mg, 1.2 mmol) was dissolved in 2 mlthionylchloride and placed in 50 ml flask. Mixture was heated to refluxfor 2 hrs and then concentrated on Rotavapor (50° C.). The acid chloride(1.2 mmol) in 5 ml dichloromethane was added to 47AKU-5 (219 mg, 1.0mmol) in 10 ml dichloromethane. After 16 hrs magnetic stirring thereaction mixture was concentrated on Rotavapor (40° C.). Crude productwas purified by flash chromatography (0-10% methanol in dichloromethane)giving 129 mg (33%) 47AKU45. HCl-salt was prepared from 2MHCl/diethylether in dichloromethane/heptane. TLC (10% methanol indichloromethane): R_(f)=0.4. HPLC-MS (Method A): M⁺=397.4(UV/MS(%)=98/89). ¹H-NMR (400 MHz, CDCl₃, rotamers): δ=7.17-6.60 (7H,m); 4.75 (1H, m); 4.51 (2H, s); 3.83 (3H, s); 3.79 (3H, s); 3.53 (2H,s); 3.27 (2H, d); 2.65 (2H, t); 2.58 (3H, s); 2.32 (3H, s); 2.24 (2H,m); 1.72 (2H, d). ¹³C-NMR (CDC₃): δ=172.8, 149.3, 148.3, 137.4, 135.0,129.8, 127.4, 125.8, 121.0, 112.2, 111.6, 56.2, 56.1, 54.6, 49.6, 46.7,44.0, 40.9, 27.0, 21.2.

Example 1292-(3,4-Methylenedioxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(47AKU46)

3,4-Methylenedioxyphenylacetic acid (216 mg, 1.2 mmol) was dissolved in2 ml thionylchloride and placed in 50 ml flask. Mixture was heated toreflux for 2 hrs and then concentrated on Rotavapor (50° C.). The acidchloride (1.2 mmol) in 5 ml dichloromethane was added to 47AKU-5 (219mg, 1.0 mmol) in 10 ml dichloromethane. After 2 hrs magnetic stirringthe reaction mixture was concentrated on Rotavapor (40° C.). Crudeproduct was purified by flash chromatography (0-10% methanol indichloromethane) giving 188 mg (49%) product. Further purification byion exchange chromatography (washout with 10% aq. NH₄OH (25%) inmethanol) yielded 149 mg (39%) 47AKU46. HCl-salt was prepared from 2MHCl/diethylether in dichloromethane/heptane. TLC (10% methanol indichloromethane): R_(f)=0.4. HPLC-MS (Method A): M⁺=381.2(UV/MS(%)=96/95). ¹H-NMR (400 MHz, CDCl₃, rotamers): δ=7.17-7.02 (4H,m); 6.77-6.51 (3H, m); 5.91 and 5.93 (2H, 2s); 4.70 (1H, m); 4.52 and4.49 (2H, 2s); 3.51 (2H, s); 3.26 (2H, d); 2.49 (3H, s); 2.33 (3H, s);2.14-1.66 (6H, m) ¹³C-NMR (CDCl₃): δ=172.5, 148.1, 146.8, 137.3, 135.1,129.8, 128.6, 125.8, 121.9, 109.4, 108.5, 101.2, 54.8, 50.2, 46.7, 44.6,41.1, 27.7, 21.2.

Example 1302-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-acetamide(47AKU49) 1-t-Butyl-4-piperidone (47AKU47)

1-Benzyl-4-piperidone (1.89 g, 10 mmol) was dissolved in 15 ml acetone.Methyliodide (0.90 ml, 15 mmol) was slowly added over 5 min. After 2 hrsmagnetic stirring additional Methyliodide (1.8 ml, 30 mmol) was added.After 1 hr magnetic stirring 20 ml diethyl-ether was added. Crudeproduct was collected by filtration and washed withacetone/diethylether. White crystals were dried under vacuum giving 806mg quartenary salt. TLC (10% methanol in dichloromethane): R_(f)=0.7.Partly dissolved salt in 5 ml water was added to 50° C. hot mixture oft-Butylamine (120 mg, 1.6 mmol) and Potassiumcarbonate (32 mg, 0.22mmol) in 3 ml ethanol. The resulting mixture was stirred and heated toreflux (˜80° C.) for 1 hr. After cooling water (20 ml) anddichloromethane (20 ml) were added. Phases were separated and aq. phasewas re-extracted with dichloromethane and ethylacetate. Combined organicphases were dried over MgSO₄ and concentrated on Rotavapor (40° C.)giving 496 mg 47AKU47. TLC (10% methanol in dichloromethane): R_(f)=0.3.¹H-NMR (400 MHz, CDCl₃): δ=2.82 (4H, t); 2.41 (4H, t); 1.12 (9H, s).¹³C-NMR (CDCl₃): δ=210.2, 54.3, 46.4, 42.4, 26.6. Crude productcontained ˜25% (¹H-NMR) starting material (1-Benzyl-4-piperidone).

4-(4-Methylbenzylamino)-1-t-butyl-piperidine (47AKU48)

4-Methylbenzylamine (268 mg, 2.2 mmol) was dissolved in 5 ml methanoland placed in 50 ml flask. 47AKU47 (305 mg, 2.0 mmol) in 5 ml methanolwas added. Acetic acid (0.3 ml) was added until pH˜5. NaCNBH₃ (250 mg,4.0 mmol) was slowly added. Gas evolution observed. After 4 hrs magneticstirring dichloromethane, 2M NaOH and water were added until pH˜10.Phases were separated and aq. phase was then re-extracted withdichloromethane and ethylacetate. Combined organic phases were driedover MgSO₄. Concentration on Rotavapor (40° C.) yielded 556 mg crude47AKU-48. TLC (20% methanol in dichloromethane): R_(f)=0.4. HPLC-MS(Method A): M⁺=261.2 (MS(%)=57).

2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-acetamide

(47AKU49)

47AKU48 (556 mg, 2.1 mmol) was placed in 50 ml flask and 5 mldichloromethane was added. 4-Methoxyphenylacetyl chloride (739 mg, 4.0mmol) in 10 ml dichloromethane was added. After 4 hrs magnetic stirringthe reaction mixture was concentrated on Rotavapor (40° C.). Crudeproduct was purified by flash chromatography (0-10% methanol indichloromethane) giving 124 mg (15%) product. Further purification byion exchange chromatography (washout with 10% aq. NH₄OH (25%) inmethanol) gave 91 mg (11%) 47AKU49. HCl-salt was prepared from 2MHCl/diethylether in dichloromethane/heptane. TLC (10% methanol indichloromethane): R_(f)=0.5. HPLC-MS (Method A): M⁺=409.4(UV/MS(%)=100/90). ¹H-NMR (400 MHz, CDCl₃): δ=7.11 (4H, m); 7.03 (2H,d); 6.79 (2H, d); 4.78 (1H, m); 4.56 (2H, s); 3.76 (3H, s); 3.53 (2H,s); 3.43 (2H, m); 2.63 (2H, m); 2.47 (2H, m); 2.31 (3H, s); 1.74 (2H,d); 1.36 (9H, s). ³C-NMR (CDC₃): δ=173.0, 158.8, 137.1, 135.3, 129.8,129.7, 127.0, 125.8, 114.3, 55.6, 55.5, 49.8, 46.5, 46.4, 40.5, 26.7,25.1, 21.2.

Example 131N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′-phenylethyl-carbamide(58AKU-1)

47AKU-5-2 (219 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane andplaced in 50 ml flask. Phenethylisocyanate (177 mg, 1.2 mmol) in 5 mldichloromethane was added. After 6 hrs magnetic stirring the reactionmixture was concentrated on Rotavapor (40° C.). Crude product waspurified by flash chromatography (0-15% methanol in dichloromethane)giving 134 mg (37%) 58AKU-1. HCl-salt was prepared from 2MHCl/diethylether in dichloromethane/heptane. TLC (10% methanol indichloromethane): R_(f)=0.5. HPLC-MS (Method A): M⁺=366.3(UV/MS(%)=99/96). ¹H-NMR (400 MHz, CDCl₃): δ=7.21-6.97 (9H, m); 4.33(1H, m); 4.26 (1H, m); 4.21 (2H, s); 3.39 (2H, q); 2.85 (2H, m); 2.67(2H, t); 2.31 (3H,s), 2.24 (3H, s), 2.06 (2H, m); 1.73-1.57 (4H, m).¹³C-NMR (CDCl₃): δ=158.7, 139.5, 137.0, 135.4, 129.7, 128.8, 128.6,126.3, 126.1, 55.6, 52.2, 46.2, 45.8, 42.2, 36.4, 30.2, 21.2.

Example 132N-Phenylethyl-N-(1-methylpiperidin-4-yl)-N′-phenethyl-carbamide(58AKU-2)

4-(2-Phenylethyl)amino-1-methylpiperidine (131 mg, 0.6 mmol) wasdissolved in 5 ml dichloromethane and placed in 50 ml flask.Phenethylisocyanate (103 mg, 0.7 mmol) in 5 ml dichloromethane wasadded. After 4 hrs magnetic stirring the reaction mixture wasconcentrated on Rotavapor (45° C.). Crude product was purified by flashchromatography (0-10% methanol in dichloromethane) giving 198 mg (90%)58AKU-1. HCl-salt was prepared from 2M HCl/diethylether indichloromethane/heptane. TLC (10% methanol in dichloromethane):R_(f)=0.3. HPLC-MS (Method A): M⁺=366.3 (UV/MS(%)=100/100). ¹H-NMR (400MHz, CDCl₃): δ=7.33-7.16 (8H, m); 7.01 (2H, m); 4.23 (1H, t); 4.04 (1H,m); 3.47 (2H, q); 3.17 (2H, t); 2.89 (2H, m); 2.78 (2H, t); 2.66 (2H,t); 2.28 (3H, s); 2.05 (2H, m); 1.79-1.59 (4H, m). ¹³C-NMR (CDCl₃):δ=157.8, 139.6, 139.0, 129.0, 128.9, 128.8, 126.8, 126.7, 55.7, 52.5,46.2, 44.6, 42.0, 37.3, 36.4, 30.5.

Example 133N-(4-Methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-N′-(4-methoxybenzyl)carbamide(58AKU-3)

47AKU-5-2 (404 mg, 1.6 mmol) was dissolved in 5 ml dichloromethane andplaced in 50 ml flask. 4-Methoxybenzylisocyanate (326 mg, 2.0 mmol) in 5ml dichloromethane was added. After 20 hrs magnetic stirring thereaction mixture was concentrated on Rotavapor (45° C.). Crude productwas purified three times by flash chromatography (0-20% methanol indichloromethane and 0-30% methanol in ethylacetate) giving 155 mg (23%)58AKU-3. HCl-salt was prepared from 2M HCl/diethylether indichloromethane/heptane. TLC (10% methanol in dichloromethane):R_(f)=0.3. HPLC-MS (Method A): M⁺=424.2 (UV/MS(%)=92183). ¹H-NMR (400MHz, CDCl₃): δ=7.10 (4H, m); 6.99 (2H, m); 6.76 (2H, m); 4.53 (1H, m);4.35 (3H, s); 4.26 (2H, d); 3.77 (3H, s); 3.09 (2H, m); 2.32 (3H, s);2.22 (2H, m); 1.81-1.54 (4H, m); 1.06 (9H, s). ¹³C-NMR (CDCl₃): δ=158.9,158.6, 137.1, 135.6, 131.9, 129.7, 128.8, 126.2, 114.0, 62.6, 55.5,53.0, 45.9, 45.7, 44.5, 31.0, 26.3, 21.2.

Example 1342-(4-Ethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(58AKU4)

4-Ethoxyphenylacetic acid (270 mg, 1.5 mmol) was dissolved in 2 mlthionylchloride and placed in 50 ml flask. Mixture was heated to refluxfor 2 hrs and then concentrated on Rotavapor (45° C.). The acid chloride(1.5 mmol) in 5 ml dichloromethane was added to 47AKU-5-2 (262 mg, 1.2mmol) in 5 ml dichloromethane. After 20 hrs magnetic stirring thereaction mixture was concentrated on Rotavapor (40° C.). Crude productwas purified by flash chromatography (0-10% methanol in dichloromethane)giving. 272 mg (60%) 58AKU4. HCl-salt was prepared from 2MHCl/diethylether in dichloromethane/heptane. TLC (10% methanol indichloromethane): R_(f)=0.4. HPLC-MS (Method A): M⁺=381.2(UV/MS(%)=98/91). ¹H-NMR (400 MHz, CDCl₃): δ=7.17-6.99 (6H, m);6.82-6.76 (2H, m); 4.73 (1H, m); 4.48 (2H, s); 3.98 (2H, q); 3.52 (2H,s); 3.22 (2H, d); 2.61 (2H, t); 2.54 (3H, s); 2.32 (3H, s); 2.14 (2H,s); 1.71 (2H, d); 1.38 (3H, t). ¹³C-NMR (CDCl₃): δ=172.9, 158.2, 137.3,135.0, 129.9, 129.8, 126.8, 125.8, 114.9, 63.7, 54.6, 49.8, 46.7, 44.1,40.6, 27.2, 21.2, 15.0.

Example 1352-(4-Butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(58AKU-5)

4-Butoxyphenylacetic acid (317 mg, 1.5 mmol) was dissolved in 2 mlthionylchloride and placed in 50 ml flask. Mixture was heated to refluxfor 2 hrs and then concentrated on Rotavapor (45° C.). The acid chloride(1.5 mmol) in 5 ml dichloromethane was added to 47AKU-5-2 (262 mg, 1.2mmol) in 5 ml dichloromethane. After 20 hrs magnetic stirring thereaction mixture was concentrated on Rotavapor (40° C.). Crude productwas purified by flash chromatography (0-10% methanol in dichloromethane)giving 230 mg (47%) 58AKU-5. HCl-salt was prepared from 2MHCl/diethylether in dichloromethane/heptane. TLC (10% methanol indichloromethane): R_(f)=0.5. HPLC-MS (Method A): M⁺=409.2(UV/MS(%)=98/93). ¹H-NMR (400 MHz, CDCl₃): δ=7.15-6.96 (6H, m); 6.78(2H, m); 4.74 (1H, m); 4.48 (2H, s); 3.91 (2H, t); 3.52 (2H, s); 3.27(2H, d); 2.72 (2H, t); 2.58 (3H, s); 2.32 (3H, s); 2.23 (2H, m); 1.72(4H, d); 1.45 (2H, m); 0.95 (3H, t). ¹³C-NMR (CDCl₃): δ=173.0, 158.4,137.3, 135.0, 129.8, 126.6, 125.8, 115.0, 67.9, 54.4, 49.5, 46.7, 43.8,40.6, 31.5, 26.8, 21.2, 19.4, 14.0.

Example 1362-(4-i-Propoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide(58AKU-6)

47AKU-29-2 (245 mg, 0.7 mmol) was dissolved in 10 ml dimethylformamideand placed in 50 ml flask. KOH (196 mg, 3.5 mmol) and Isopropylbromide(200 μl, 2.1 mmol) were added. Mixture was heated to 50° C. and stirredfor 24 hrs. After cooling water and ethylacetate were added. Phases wereseparated and aq. phase was then re-extracted with dichloromethane.Combined organic phases were washed with brine, dried over MgSO₄ andconcentrated on Rotavapor (40° C.) giving 188 mg. Crude product waspurified by flash chromatography (0-10% methanol in dichloromethane)yielding 136 mg (49%) 58AKU-6. HCl-salt was prepared from 2MHCl/diethylether in dichloromethane/heptane. TLC (10% methanol indichloromethane): R_(f)=0.3. HPLC-MS (Method B): M⁺=395(UV/MS(%)=95/91). ¹H-NMR (400 MHz, CDCl₃, rotamers): δ=7.23-7.01 (6H,m); 6.79 (2H, m); 4.60 (1H, m); 4.51 (1H, m); 4.44 (1H, s); 3.77 (1H,s); 3.52 (1H, s); 2.83 (2H, m); 2.76 (2H, m); 2.28 and 2.34 (3H, 2s);2.19 and 2.22 (3H, 2s); 2.05 (1H, m);. 1.86-1.55 (4H, m); 1.32 (6H, d).¹³C-NMR (CDCl₃): δ=172.6, 157.0, 137.1, 135.6, 129.8, 129.7, 125.8,116.2, 70.1, 55.3, 51.6, 46.6, 46.1, 40.8, 29.6, 22.3, 21.2.

Example 137 Receptor Selection and Amplification (R-SAT) Assays

The functional receptor assay, Receptor Selection and AmplificationTechnology (R-SAT), was used (with minor modifications from thatpreviously described U.S. Pat. No. 5,707,798) to screen compounds forefficacy at the 5-HT2A receptor. Briefly, NIH3T3 cells were grown in 96well tissue culture plates to 70-80% confluence. Cells were transfectedfor 12-16 hours with plasmid DNAs using superfect (Qiagen Inc.) as permanufacture's protocols. R-SAT's were generally performed with 50ng/well of receptor and 20 ng/well of Beta-galactosidase plasmid DNA.All receptor and G-protein constructs used were in the pSI mammalianexpression vector (Promega Inc) as described in U.S. Pat. No. 5,707,798.The 5HT2A receptor gene was amplified by nested PCR from brain cDNAusing the oligodeoxynucleotides based on the published sequence (seeSaltzman et. al. Biochem. Biophys. Res. Comm. 181:1469-78 (1991)).Large-scale transfections, cells were transfected for 12-16 hours, thentrypsinized and frozen in DMSO. Frozen cells were later thawed, platedat 10,000-40,000 cells per well of a 96 well plate that contained drug.With both methods, cells were then grown in a humidified atmosphere with5% ambient CO2 for five days. Media was then removed from the plates andmarker gene activity was measured by the addition of thebeta-galactosidase substrate ONPG (in PBS with 5% NP-40). The resultingcolorimetric reaction was measured in a spectrophotometric plate reader(Titertek Inc.) at 420 nM. All data were analyzed using the computerprogram XLFit (IDBSm). Efficacy is the percent maximal repressioncompared to repression by a control compound (ritanserin in the case of5HT2A). pIC50 is the negative of the log(IC50), where IC50 is thecalculated concentration in Molar that produces 50% maximal repression.The results obtained for several compounds of the invention arepresented in Table 4, below. TABLE 4 Efficiency and pIC50 of Compoundsat the 5-HT2A Receptor Compared to Ritanserin Compound Percent EfficacypIC50 26HCH17 94 8.3 26HCH65 103 8.2 26HCH66-05 126 8.1 26HCH79-5 94 8.226HCH79-6 83 8.3 26HCH79-10 102 7.8 26HCH71B 124 7.9 42ELH45 108 9.050ELH27 108 8.7 47AKU-7 120 8.1 42ELH80 122 8.5 42ELH79 110 8.5 42ELH91108 8.0 42ELH85 118 7.8 42ELH75 109 8.3 47AKU-12 112 8.1 47AKU-8 113 8.147AKU-22 117 7.9 47AKU-21 117 7.9 47AKU-20 120 8.0 50ELH8 129 7.850ELH68 96 8.4 50ELH65 92 7.9 47AKU-44 112 8.5 57MBT12B 75 7.7 58AKU-4110 9.6 58AKU-3 111 8.1 58AKU-5 99 9.5 58AKU-6 101 9.8 57MBT54B 95 7.950ELH95B 119 8.0 50ELH93E 72 8.1 50ELH93D 58 7.8 50ELH93A 106 8.763ELH1A 104 8.3 50ELH89 111 9.7 63ELH20 95 9.0 57MBT70-8D 119 7.757MBT70-5D 105 8.4 57MBT70-4D 98 8.5 57MBT70-3D 87 8.9 57MBT70-2D 1058.2 57MBT70-1D 120 7.9 63ELH21 100 8.5 57MBT62B 119 7.9 57MBT70-6E 1158.0

Example 138 Selectivity Profile for2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamidehydrochloride

The R-SAT assay (described above in example 137) was used to investigatethe selectivity of2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamidehydrochloride. The results from a broad profiling of this compound at avariety of receptors are reported in Table 4 below. NR means NoResponse, i.e. the compound investigated showed no effect at thereceptor studied. TABLE 4 Selectivity of2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide RECEPTOR ASSAY pEC50/pIC50 5-HT_(1A)agonist NR antagonist NR 5-HT_(1B) agonist NR antagonist NR 5-HT_(1D)agonist NR antagonist NR 5-HT_(1E) agonist NR antagonist NR 5-HT_(1F)agonist NR antagonist NR 5-HT_(2A) agonist NR inverse agonist 8.85-HT_(2B) agonist NR inverse agonist 6.9 5-HT_(2C) agonist NR inverseagonist 7   5-HT₄ agonist NR inverse agonist NR 5-HT₆ agonist NR Inv.Agonist 6.8 5-HT7 agonist NR inverse agonist 6.9 m1 agonist NRantagonist NR m2 agonist NR antagonist NR m3 agonist NR antagonist NR m4agonist NR antagonist NR m5 agonist NR antagonist NR D1 agonist NRantagonist NR D2 agonist NR antagonist NR D3 agonist NR antagonist NR D5agonist NR antagonist NR Histamine 1 agonist NR Inv. agonist NRHistamine 2 agonist NR antagonist NR Histamine 3 agonist NR antagonistNR alpha-1A(a/c) agonist NR antagonist NR alpha-1B agonist NR In.Agonist NR alpha-2A agonist NR antagonist NR alpha-2B agonist NRantagonist NR alpha-2C agonist NR antagonist NR beta 1 agonist NRantagonist NR beta 2 agonist NR antagonist NR endothelinB agonist NRCCK-A agonist NR NK-1 agonist NR Vasopressin1A agonist NR K-opiodagonist NR

Example 139 In Vivo Pharmacology of2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamidehydrochloride(AC-90,179)

Methods

Animals and Apparatus

Instruments) were used for rat experiments (details on startle apparatusand measures, see Male Non-Swiss Albino mice and male Sprague-Dawleyrats (Harlan Sprague-Dawley) were housed (4 mice/cage; 2 rats/cage) inrooms with temperature and humidity controlled and water and food(Harlan Teklad) freely available. Mice were kept on a 12-hr light:darkcycle, whereas rats were kept on a 12-hr reverse light:dark cycle. Forlocomotor and observation experiments in mice, plastic 20×20×30 cmactivity cages were equipped with photocell beams (AccuScanInstruments). Startle chambers (San Diego Instruments) were used for ratexperiments (for details on startle apparatus and measures, see Mansbachet al., (1988) Psychopharmacology 94:507-14).

Procedure

Observation for Head Twitches

Mice were treated with 2.5 mg/kg DOI i.p. Five min later, mice weretreated with AC-90179 s.c. and placed into activity cages. Ten minlater, mice were observed using a repeated sampling technique. Eachmouse was observed for 10 sec and rated for presence (1) or absence (0)of head twitch behavior for a total of 6 observations in. 15 min and atotal head twitch score of 0-6. Each dose combination was tested in aseparate group of animals (n=8) and the experimenter was blind to drugconditions. Head twitch scores were averaged followed by analysis ofvariance (ANOVA) and post-hoc Dunnett's t-test comparisons.

Locomotor Activity

For hyperactivity experiments, mice were treated with 0.3 mg/kgdizocilpine or 3.0 mg/kg d-amphetamine i.p. 15 min before the session.Five minutes after the pretreatment, mice were treated with AC-90179s.c. and placed into the activity cages. For spontaneous activity,AC-90179 was administered alone. Locomotor data were collected during a15 min session without habituation in a lit room. Each dose combinationwas tested in a separate group of animals (n=8). Distance traveled (cm)was calculated and averaged followed by ANOVA and post-hoc Dunnett'st-test comparisons.

Startle Testing

Rats were tested and groups (n=10) matched for levels of startlereactivity and prepulse inhibition (PPI; see Mansbach et al., (1988)Psychopharmacology 94:507-14). Two days later, test sessions started andconsisted of a 5-min acclimation period with a constant background noise(65 dB), followed by 60 presentations of acoustic stimuli to measureacoustic startle responses. The 60 trials consisted of: twenty two 40-mspresentations of a 120 dB broadband pulse, ten 20-ms presentations ofeach prepulse intensity (68, 71, 77 dB) 100 ms prior to a 40-msecpresentation of a 120 dB broadband pulse, and 8 NOSTIM trials in whichno stimuli were delivered in order to assess general motor activation inthe rats. Thirty min before testing, rats were treated with sterilewater (s.c.), risperidone (1.0 mg/kg, i.p.), or AC-90179 (s.c.). Fivemin later, rats were administered DOI (0.5 mg/kg, s.c.) or 0.9% saline(s.c.). One-week later, rats were administered the same pretreatmentdrug or vehicle and crossed over to receive the treatment opposite tothat they received the previous week. Startle magnitudes and percent PPIfor the three prepulse intensities were calculated as describedelsewhere (Bakshi, et al., (1994) J. Pharmacol. Exp. Ther. 271:787-94)and ANOVAs with repeated measures performed.

Results

To further characterize the clinical utility of a selective 5-HT2Areceptor inverse agonist as a novel antipsychotic agent, AC-90179 wastested in head twitch, locomotor and pre pulse inhibition behavioralmodels. DOI-treated (2.5 mg/kg, i.p., 15 min) mice exhibited an averagehead twitch score of 2.6 (+0.3, S.E.M.). AC-90179 (0.1-30 mg/kg, s.c.,10 min) caused a dose-related decrease in DOI-induced head-twitches witha minimum effective dose of 1 mg/kg and with higher doses completelyeliminating head twitch behavior (FIG. 2A).

In the locomotor experiments (FIG. 2B), mice traveled an average of 794cm (±122 S.E.M.) after vehicle administration. Dizocilpine (0.3 mg/kg,i.p., 15 min) and d-amphetamine (3.0 mg/kg, i.p., 15 min) causedincreases in distance traveled with averages of 2625 cm (±312) and 3367cm (±532), respectively. AC-90179 (0.3-10 mg/kg, s.c., 10 min)attenuated the hyperactivity induced by dizocilpine, but not byd-amphetamine. The minimum effective dose against dizocilpine was 1mg/kg, whereas AC-90179 reduced spontaneous locomotor activity only atthe highest dose tested (30 mg/kg).

The 3-way repeated measures ANOVA on the PPI data from the AC-90179groups revealed an overall effect of treatment [F(1,37)=27.73, p=<0.01]and a treatment by pretreatment interaction [F(3,37)=8.22, p<0.01] (FIG.2C). DOI significantly disrupted PPI, and AC-90179 was effective inrestoring this disruption especially at the higher doses. AC-90179 didnot affect PPI on its own, with no significant effect of pretreatment(p>0.05) on percent PPI. Risperidone was used as a positive controlbecause previous studies in our laboratory have suggested that it iseffective in blocking the PPI-disruptive effects of DOI. The 3-wayrepeated measures ANOVA on the PPI data from the risperidone group alsorevealed a significant effect of treatment [F(1,18)=14.08, p<0.01] and atreatment by pretreatment interaction [F(1,18)=24.48, p<0.01). Aspredicted, risperidone was also effective in restoring PPI inDOI-treated rats. Risperidone also had no effect on PPI by itself, asevidenced by a lack of a pretreatment effect (p>0.05). Since there wereno significant interactions with prepulse intensity, the data werecollapsed across the three prepulse intensities for graphical purposes.

Since there was a significant pretreatment by treatment interaction,pair-wise 2-way repeated measures ANOVAs were conducted on the saline-and DOI-treated groups. In the vehicle-treated rats, there was no effectof AC-90179 (p>0.025) or risperidone (p>0.025) on PPI. In theDOI-treated groups, there were significant effects of AC-90179[F(3,37)=5.68, p<0.01] and risperidone [F(1,18)=16.73, p<0.01) onpercent PPI.

The 3-way repeated measures ANOVA on startle magnitude from the AC-90179groups revealed a significant effect of pretreatment [F(3,37)=2.89,p=0.048) and treatment [F(1,37)=10.27, p<0.01] on startle magnitude, butno treatment by pretreatment interaction (p>0.05; FIG. 1, panel Cinset). Risperidone, on the other hand, had no effect on startlemagnitude (p>0.05).

Example 140 In Vivo Pharmacology of Additional Compounds

The effect of various compounds on head twitch behavior in mice treatedwith DOI was observed as described above in Example 139. The results aresummarized below in Table 5.

The effect of various compounds on head twitch behavior in mice treatedwth DOI was observed as described in Example 139. Animals received0.1-30 mg/kg of the compound indicated via subcutaneous injection. MEDindicates the minimum effective dose at which a statisticallysignificant reduction in head twitching score (described above) wasobserved. MED=minimum effective dose in vivo. TABLE 5 Comparison OfAnalogs For Their Ability To Attenuate DOI-Induced Head Twitches InMice. Compound MED 26HCH17 30 44ELH45 30 50ELH27 1 42ELH80 ≦10 42ELH79≦10 47AKU-7 ≦10 42ELH85 ≦10 47AKU-8 ≦10 47AKU-12 ≦10 47AKU-13 ≦1042ELH91 >10 42ELH90 ˜10 47AKU-20 ≦10 47AKU-19 >10 47AKU-22 ≦1047AKU-21 >10 42ELH75 ≦10 47AKU-11 ˜10 47AKU-14 ≦10 47AKU-18 ≧10 50ELH6≦10 47AKU-33 ≧10 47AKU-25 >10 50ELH65 ≦10 50ELH68 ≦10 47AKU-49 ≦1047AKU-44 ≦10 58AKU-4 ≦10 58AKU-5 ≦1 50ELH93A ≦10 58AKU-6 ≦10 63ELH20 ≦1063ELH21 ≦10MED = minimum effective dose in vivo.

The invention described and claimed herein is not to be limited in scopeby the specific embodiments herein disclosed, since these embodimentsare intended as illustrations of several aspects of the invention. Anyequivalent embodiments are intended to be within the scope of thisinvention. Indeed, various modifications of the invention in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description. Such modifications are alsointended to fall within the scope of the appended claims.

The disclosures of all references cited herein are incorporated byreference in their entireties.

1. A compound of formula (I)

wherein Z is

in which R is a hydrogen, a cyclic or straight-chained or branchedacyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkylgroup, or an aralkyl or heteroaralkyl group; n is 0, 1, or 2; X₁ ismethylene, vinylene, or an NH or N(lower alkyl) group; and X₂ ismethylene, or, when X₁ is methylene or vinylene, X₂ is methylene or abond; or when X₁ is methylene, X₂ is O, S, NH, or N(lower alkyl) or abond; Y₁ is methylene and Y₂ is methylene, vinylene, ethylene,propylene, or a bond; or Y₁ is a bond and Y₂ is vinylene; or Y₁ isethylene and Y₂ is O, S, NH, or N(lower alkyl); Ar₁ and Ar₂independently are unsubstituted or substituted aryl or heteroarylgroups, provided that Ar₁ and Ar₂ are not simultaneously unsubstitutedphenyl; and W is oxygen or sulfur.
 2. A compound according to claim 1,wherein Y₁ is methylene and Y₂ is a bond, methylene, ethylene, orvinylene; or Y₁ is ethylene and Y₂ is O or S; and X₁ is methylene and X₂is a bond, methylene, O, or S; or X₁ is NH or N(lower alkyl) and X₂ ismethylene.
 3. A compound according to claim 2, wherein Z is

and W is oxygen.
 4. A compound according to claim 3, wherein Ar₁ and Ar₂independently are mono- or disubstituted phenyl groups.
 5. A compoundaccording to claim 4, wherein R is a hydrogen, a lower alkyl group, acyclic organyl group, or a substituted or unsubstituted aralkyl orheteroaralkyl group; n is 1; Y₁ is methylene, Y₂ is a bond, methylene,ethylene, or vinylene; X₁ is methylene and X₂ is a bond, or. X₁ is NH orN(lower alkyl) and X₂ is methylene; and Ar₁ and Ar₂ are phenyl groups,independently p-substituted with groups selected from lower alkyl, loweralkoxy and halogen.
 6. A compound according to claim 1, having a formula(II)

wherein R^(N) is hydrogen, lower alkyl, aralkyl, or heteroaralkyl;Ar^(L) is selected from lower alkyl, lower alkoxy and halogen Ar^(R) isselected from lower alkyl, lower alkoxy and halogen; k is 1 or 2 and A⁻is a suitable anion.
 7. The compound according to claim 1, wherein thecompound is selected from the group consisting of:N-(1-(1-methylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-(2,2-dimethylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-pentylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-hexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-cyclohexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-cyclopentylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-cyclobutylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-cyclopropylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-(cyclopentylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-(cyclobutylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-(cyclopropylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-(2-hydroxyethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-(3-hydroxypropyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-((4-methylphenyl)methyl)-N-(piperidin-4-yl)-N′-phenylmethylcarbamide;N-((4-methylphenyl)methyl)-N-(1-(2-methylpropyl)piperidin-4-yl)-N′-phenylmethylcarbamide;N-(1-((2-bromophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide;N-(1-((4-hydroxy-3-methoxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide;N-(1-((5-ethylthien-2-yl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide;N-(1-(imidazol-2-ylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide;andN-(1-(cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide.8. A compound of formula (I)

wherein Z is

in which R is a hydrogen, a cyclic or straight-chained or branchedacyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkylgroup, or an aralkyl or heteroaralkyl group; and n is 0, 1, or 2; X₁ ismethylene, vinylene, or an NH or N(lower alkyl) group; and X₂ ismethylene, or, when X₁ is methylene or vinylene, X₂ is methylene or abond; or when X₁ is methylene, X₂ is O, S, NH, or N(lower alkyl) or abond; Y₁ is methylene and Y₂ is methylene, vinylene, ethylene,propylene, or a bond; or Y₁ is a bond and Y₂ is vinylene; or Y₁ isethylene and Y₂ is O, S, NH, or N(lower alkyl); Ar₁ and Ar₂ aredifferent unsubstituted or substituted aryl or heteroaryl groups; and Wis oxygen or sulfur.
 9. A compound according to claim 8, wherein Y₁ ismethylene and Y₂ is a bond, methylene, ethylene, or vinylene; or Y₁ isethylene and Y₂ is O or S; and X₁ is methylene and X₂ is a bond,methylene, O, or S; or X₁ is NH or N(lower alkyl) and X₂ is a methylene.10. A compound according to claim 9, wherein Z is

and W is oxygen.
 11. A compound according to claim 10, wherein Ar₁ andAr₂ independently are mono- or disubstituted phenyl groups.
 12. Acompound according to claim 11, wherein R is a hydrogen, a lower alkylgroup, a cyclic organyl group, or an, optionally substituted, alalkyl orheteroaralkyl group; n is 1; Y₁ is methylene, Y₂ is a bond, methylene,ethylene, or vinylene; X₁ is methylene and X₂ is a bond, or X₁ is NH orN(lower alkyl) and X₂ is methylene; and Ar₁ and Ar₂ are phenyl groups,independently p-substituted with groups selected from alkyl, loweralkoxy and halogen.
 13. A compound according to claim 7, having aformula (II):

wherein R^(N) is hydrogen, lower alkyl, aralkyl, or heteroaralkyl;Ar^(L) is selected from lower alkyl lower alkoxy and halogen Ar^(R) isselected from lower alkyl, lower alkoxy and halogen; k is 1 or 2 and A⁻is a suitable anion.
 14. A pharmaceutical composition comprising aneffective amount of a compound of formula (I):

wherein Z is

in which R is a hydrogen, a cyclic or straight-chained or branchedacyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkylgroup, or an aralkyl or heteroaralkyl group; and n is 0, 1, or 2; X₁ ismethylene, vinylene, or an NH or N(lower alkyl) group; and X₂ ismethylene, or, when X₁ is methylene or vinylene, X₂ is methylene or abond; or when X₁ is methylene, X₂ is O, S, NH, or N(lower alkyl) or abond; Y₁ is methylene and Y₂ is methylene, vinylene, ethylene,propylene, or a bond; or Y₁ is a bond and Y₂ is vinylene; or Y₁ isethylene and Y₂ is O, S, NH, or N(lower alkyl); Ar₁ and Ar₂independently are unsubstituted or substituted aryl or heteroarylgroups, provided that Ar₁ and Ar₂ are not simultaneously phenyl; and Wis oxygen or sulfur; or a pharmaceutically acceptable salt, ester orprodrug thereof, and a pharmaceutically acceptable diluent or excipient.15. A method of inhibiting an activity of a monoamine receptorcomprising contacting the monoamine receptor or a system containing themonoamine receptor with an amount of one or more of the compounds ofclaim 1 that is effective in inhibiting the activity of the monoaminereceptor.
 16. The method of claim 15 wherein the monoamine receptor is aserotonin receptor.
 17. The method of claim 16 wherein the serotoninreceptor is the 5-HT2A subclass.
 18. The method of claim 16 wherein theserotonin receptor is in the central nervous system.
 19. The method ofclaim 16 wherein the serotonin receptor is in the peripheral nervoussystem.
 20. The method of claim 16 wherein the serotonin receptor is inblood cells or platelets.
 21. The method of claim 16 wherein theserotonin receptor is mutated or modified.
 22. The method of claim 15wherein the activity is signaling activity.
 23. The method of claim 15wherein the activity is constitutive.
 24. The method of claim 15 whereinthe activity is associated with serotonin receptor activation.
 25. Amethod of inhibiting an activation of a monoamine receptor comprisingcontacting the monoamine receptor or a system containing the monoaminereceptor with an amount of a compound of one or more of the compounds ofclaim 1 that is effective in inhibiting the activation of the monoaminereceptor.
 26. The method of claim 25 wherein the activation is by anagonistic agent.
 27. The method of claim 26 wherein the agonistic agentis exogenous.
 28. The method of claim 26 wherein the agonistic agent isendogenous.
 29. The method of claim 25 wherein the activation isconstitutive.
 30. The method of claim 25 wherein the monoamine receptoris a serotonin receptor.
 31. The method of claim 30 wherein theserotonin receptor is the 5-HT2A subclass.
 32. The method of claim 30wherein the serotonin receptor is in the central nervous system.
 33. Themethod of claim 30 wherein the serotonin receptor is in the peripheralnervous system.
 34. The method of claim 30 wherein the serotoninreceptor is in blood cells or platelets.
 35. The method of claim 30wherein the serotonin receptor is mutated or modified.
 36. A method oftreating a disease condition associated with a monoamine receptorcomprising administering to a subject in need of such treatment atherapeutically effective amount of one or more of the compounds ofclaim
 1. 37. The method of claim 36 wherein the disease condition isselected from the group consisting of schizophrenia, psychosis,migraine, hypertension, thrombosis, vasospasm, ischemia, depression,anxiety, sleep disorders and appetite disorders.
 38. The method of claim36 wherein the disease condition is associated with dysfunction of amonoamine receptor.
 39. The method of claim 36 wherein the diseasecondition is associated with activation of a monoamine receptor.
 40. Themethod of claim 36 wherein the disease condition is associated withincreased activity of monoamine receptor.
 41. The method of claim 36wherein the monoamine receptor is a serotonin receptor
 42. The method ofclaim 41 wherein the serotonin receptor is the 5-HT2A subclass.
 43. Themethod of claim 41 wherein the serotonin receptor is in the centralnervous system.
 44. The method of claim 41 wherein the serotoninreceptor is in the peripheral nervous system.
 45. The method of claim 41wherein the serotonin receptor is in blood cells or platelets.
 46. Themethod of claim 41 wherein the serotonin receptor is mutated ormodified.
 47. A method of treating schizophrenia comprisingadministering to a subject in need of such treatment a therapeuticallyeffective amount of a compound of one or more of the compounds ofclaim
 1. 48. A method of treating migraine comprising administering to asubject in need of such treatment a therapeutically effective amount ofa compound of one or more of the compounds of claim
 1. 49. A method oftreating psychosis comprising administering to a subject in need of suchtreatment a therapeutically effective amount of a compound of one ormore of the compounds of claim
 1. 50. A method for identifying a geneticpolymorphism predisposing a subject to being responsive to one or moreof the compounds of claim 1, comprising: administering to a subject atherapeutically effective amount of the compound; measuring the responseof said subject to said compound, thereby identifying a responsivesubject having an ameliorated disease condition associated with amonoamine receptor; and identifying a genetic polymorphism in theresponsive subject, wherein the genetic polymorphism predisposes asubject to being responsive to the compound.
 51. The method of claim 50wherein the ameliorated disease condition is associated with the 5-HTclass or 5-HT2A subclass of monoaminergic receptors.
 52. A method foridentifying a subject suitable for treatment with one or more of thecompounds of claim 1, comprising detecting the presence of apolymorphism in a subject wherein the polymorphism predisposes thesubject to being responsive to the compound, and wherein the presence ofthe polymorphism indicates that the subject is suitable for treatmentwith one or more of the compounds of claim
 1. 53. The compound accordingto claim 1, wherein the compound is selected from the group consistingof:N-(1-((4-fluorophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N′-phenylmethylcarbamide;N-((4-methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;N-((4-methylphenyl)methyl)-N-(1-methylpiperidin-4-yl)-4-methoxyphenylacetamide;N-(1-ethylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-((4-methylphenyl)methyl)-N-(1-propylpiperidin-4-yl)-4-methoxyphenylacetamide;N-(1-butylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-(3,3-dimethylbutyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-(cyclohexylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-((4-methylphenyl)methyl)-N-(1-(2-methylpropyl)piperidin-4-yl)-4-methoxyphenylacetamide;N-((4-methylphenyl)methyl)-N-(1-((4-methylphenyl)methyl)piperidin-4-yl)-4-methoxyphenylacetamide;N-(1-((4-hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(1-((2-hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;N-(3-phenylpropyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;N-(2-phenylethyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;N-((2-methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide:N-((2-chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;N-((3,4-di-methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;N-((4-fluorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;N-((2,4-di-chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;andN-((3-methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide.54. The compound according to claim 1, wherein the compound is selectedfrom the group consisting of:N-((3-bromophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;N-(1-(phenylmethyl)piperidin-4-yl)-N-(3-phenyl-2-propen-1-yl)-4-methoxyphenylacetamide;N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-phenylacetamide;N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-3-phenylpropionamide;N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-(phenylthio)acetamide;N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-phenoxyacetamide;N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-(4-chlorophenoxy)acetamide;N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-3-methoxyphenylacetamide;N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-4-fluorophenylacetamide;N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-2,5-di-methoxyphenylacetamide;N-((4-methylphenyl)methyl)-N-(1-piperidin-4-yl)-4-chlorophenylacetamide;N-((4-methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-N′-phenylmethylcarbamide;N-((4-methylphenyl)methyl)-N-(1-(phenylmethyl)pyrrolidin-3-yl)-4-methoxyphenylacetamide;2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(piperidin-4-yl)acetamide;2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperidin-4-yl)acetamide;2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-ethylpiperidin-4-yl)acetamide.2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-isopropylpiperidin-4-yl)acetamide;2-(4-methoxyphenyl)-N-(4-chlorobenzyl)-N-(piperidin-4-yl)acetamide; and2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-cyclopentylpiperidin-4-yl)acetamide.55. The compound according to claim 1, wherein the compound is selectedfrom the group consisting of:2-(4-methoxyphenyl)-N-(4-chlorbenzyl)-N-(1-isopropylpiperidin-4-yl)acetamide;2-(phenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-fluorophenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-Methoxyphenyl)-N-(4-trifluoromethylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-Trifluoromethylphenyl)-N-(4-trifluoromethylbenzyl)-AT-(1-methylpiperidin-4-yl)acetamide;2-(4-Fluorophenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-Methoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(phenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-Trifluoromethylphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-trifluoromethylphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;2-Phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;2-(4-Chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;2-(4-Methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;2-(4-trifluoromethylphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;2-Phenyl-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;2-(4-Chlorophenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(l-methylpiperidin-4-yl)acetamide;2-(4-Methoxyphenyl)-N-[4-(methoxycarbonyl)benzyl]-N-(1-methylpiperidin-4-yl)acetamide;2-(4methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(4-chloromethyl-2-thiazolylmethyl)piperidin-4-yl]acetamide;2-(4 methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3(1,3dihydro-2H-benzimidazol-2-on-1-yl) propyl]piperidin-4-yl}acetamide; and2-(4-methoxyphenyl)-N-(2-4(fluorophenyl)ethyl)-N-(1-methylpiperidin-4-yl)acetamide.56. The compound according to claim 1, wherein the compound is selectedfrom the group consisting of:2-(4-methoxyphenyl)-N-[2-(2,5-dimethoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide;2-(4-methoxyphenyl)-N-[2-(2,4-dichlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide;2-(4-methoxyphenyl)-N-[2-(3-chlorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide;2-(4-methoxyphenyl)-N-[2-(4-methoxyphenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide;2-(4-methoxyphenyl)-N-[2-(3-fluorophenyl)ethyl]-N-(1-methylpiperidin-4-yl)acetamide;2-(4-ethoxyphenyl)-N-[2-(4-fluorophenethyl]-N-(1-methylpiperidin-4-yl)acetamide;2-(4-ethoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2-hydroxyethoxy)ethyl]piperidin-4-yl}acetamide;2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-((2-chloro-5-thienyl)methyl)piperidin-4-yl]acetamide;2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(2-(imidazolidinon-1-yl)ethyl)piperidin-4-yl]acetamide;2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(2,4(1H,3H)quinazolinedion-3-yl)ethyl]piperidin-4-yl}acetamide;2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(1,3-dioxolan-2-yl)ethyl]piperidin-4-yl}acetamide;2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[2-(3-indolyl)ethyl]piperidin-4-yl}acetamide;2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-{1-[3-(1,2,4-triazol-1-yl)propyl]piperidin-4-yl}acetamide;2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-benzofurazanylmethyl)piperidin-4-yl]acetamide;2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-chlorobenzo[b]thien-3-ylmethyl)piperidin-4-yl]acetamide;2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-[1-(5-phenyl-1,2,4-oxadiazol-3-ylmethyl)piperidin-4-yl]acetamide;2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-isopropylpiperidin-4-yl)-acetamide;2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-ethylpiperidin-4-yl)-acetamide;and 2-Phenyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide.57. The compound according to claim 1, wherein the compound is selectedfrom the group consisting of:2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclopentylpiperidin-4-yl)-acetamide;2-(4-Fluorophenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-(2-hydroxyethyl)-piperidin-4-yl)-acetamide;2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-yl)-acetamide;2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-cyclobutylpiperidin-4-yl)-acetamide;N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′-benzyl-carbamide;N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′-phenyl-carbamide;N-Phenethyl-N-(1-methylpiperidin-4-yl)-N′-benzyl-carbamide;2-Phenyl-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;2-(4-Trifluoromethylphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;2-(4-Fluorophenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;2-(4-Methoxyphenyl)-N-(4-methoxybenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;2-(4-Methylphenyl)-N-(4-chlorobenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;2-(4-Hydroxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-acetamide;N-Phenethyl-N-(1-methylpiperidin-4-yl)-N′-phenyl-carbamide;N-(3-Phenylpropyl)-N-(1-methylpiperidin-4-yl)-N′-benzyl-carbamide;N-(3-Phenylpropyl)-N-(1-methylpiperidin-4-yl)-N′-phenyl-carbamide;2-(4-Methoxyphenyl)-2,2-ethylene-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;and2-(4-Methoxyphenyl)-N-alpha-methylbenzyl-N-(1-methylpiperidin-4-yl)acetamide.58. The compound according to claim 1, wherein the compound is selectedfrom the group consisting of:2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-acetamide;and2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(8-methyl-8-aza-bicyclo[3.2.1]octen-3-yl)-acetamide.59. The compound according to claim 1, wherein the compound is selectedfrom the group consisting of:2-Phenyl-2-ethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;N-Phenethyl-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)-amine;2-(4-Methoxyphenyl)-N-(1-indanyl)-N-(1-methylpiperidin-4-yl)acetamide;N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-methoxybenzyl)-carbamide;2-(3,4-dimethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(3,4-Methylenedioxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-acetamide;N-(4-Methylbenzyl)-N-(1-methylpiperidin-4-yl)-N′-phenethyl-carbamide;N-Phenethyl-N-(1-methylpiperidin-4-yl)-N′-phenethyl-carbamide;N-(4-Methylbenzyl)-N-(1-t-butylpiperidin-4-yl)-N′-(4-methoxybenzyl)-carbamide;2-(4-Ethoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-Butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-i-Propoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-t-Butoxyphenyl)-N-(4-methylbenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-Butoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-Propoxyphenyl)-N-(4-flourobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;2-(4-i-Propoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide;and2-(4-t-Butoxyphenyl)-N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)acetamide.60. A compound according to claim 5, wherein R is a lower alkyl group;n=1; Y₁ is methylene, Y₂ is a bond, methylene, ethylene, or vinylene; X₁is methylene and X₂ is a bond, or X₁ is NH or N(lower alkyl) and X₂ ismethylene; and Ar₁ and Ar₂ are phenyl groups, independentlyp-substituted with groups selected from lower alkyl, lower alkoxy andhalogen.
 61. A compound according to claim 60, wherein R is a loweralkyl group; n=1; Y₁ is methylene, Y₂ is a bond; X₁ is NH or N(loweralkyl) and X₂ is methylene; and Ar₁ and Ar₂ are phenyl groups,independently p-substituted with groups selected from lower alkyl, loweralkoxy and halogen.
 62. A compound according to claim 61, wherein Ar₁ isa p-substituted phenyl group, wherein said phenyl group is substitutedwith a halogen; and Ar₂ is a p-substituted phenyl group, wherein saidphenyl group is substituted with a lower alkoxy.
 63. A compoundaccording to claim 62, wherein the halogen of Ar₁ is a fluoro atom; andthe lower alkoxy of Ar₂ is a C₁₋₆ cyclic organyl group attached to Ar₂via an oxygen atom.
 64. A compound according to claim 63, wherein theC₁₋₆ cyclic organyl group is attached to the oxygen atom via asubstituted or unsubstituted —(CH₂)— or —(CH₂CH₂)—.
 65. A compoundaccording to claim 63, wherein the C₁₋₆ cyclic organyl group is attachedto the oxygen atom via one or more carbon atoms appended from the C₁₋₆cyclic organyl group.
 66. A method of alleviating a condition associatedwith non-selective antipsychotic compounds comprising administering atherapeutically effective amount of a one or more of the compounds ofclaim 1 to a subject suffering from said condition.
 67. The methodaccording to claim 66, wherein the compound of claim 1 is a selectiveantagonist or inverse agonist of a 5-HT2A receptor.
 68. The method ofaccording to claim 66, wherein the compound of claim 1 has little to noactivity on other monamine receptors.
 69. The method according to claim68, wherein one of the other monamine receptors is a dopamine D2receptor.
 70. The method according to claim 66, wherein Z is

and W is oxygen in the compound of claim
 1. 71. The method according toclaim 66, wherein R is a hydrogen, a lower alkyl group, a cyclic organylgroup, or a substituted or unsubstituted aralkyl or heteroaralkyl group;n is 1; Y₁ is methylene, Y₂ is a bond, methylene, ethylene, or vinylene;X₁ is methylene and X₂ is a bond, or X₁ is NH or N(lower alkyl) and X₂is methylene; and Ar₁ and Ar2 are phenyl groups, independentlyp-substituted with groups selected from lower alkyl, lower alkoxy andhalogen in the compound of claim
 1. 72. A method of alleviating acondition which is a side effect which can arise in an individual whotakes an antipsychotic compound which possess broad activity at multiplemonamine receptors subtypes, comprising administering a therapeuticallyeffective amount of one or more of the compounds of claim 1 to subjectsuffering from said condition.
 73. The method according to claim 72,wherein the compound of claim 1 is a selective antagonist or inverseagonist of a 5-HT2A receptor.
 74. The method of according to claim 72,wherein the compound of claim 1 has little to no activity on othermonamine receptors.
 75. The method according to claim 74, wherein one ofthe other monamine receptors is a dopamine D2 receptor.
 76. The methodaccording to claim 72, wherein Z is

and W is oxygen in the compound of claim
 1. 77. The method according toclaim 72, wherein R is a hydrogen, a lower alkyl group, a cyclic organylgroup, or a substituted or unsubstituted aralkyl or heteroaralkyl group;n is 1; Y₁ is methylene, Y₂ is a bond, methylene, ethylene, or vinylene;X₁ is methylene and X₂ is a bond, or X₁ is NH or N(lower alkyl) and X₂is methylene; and Ar₁ and Ar₂ are phenyl groups, independentlyp-substituted with groups selected from lower alkyl, lower alkoxy andhalogen in the compound of claim 1
 78. The compound according to claim1, wherein X₁ is an NH or N(lower alkyl) group; and W is oxygen.
 79. Thecompound according to claim 8, wherein X₁ is an NH or N(lower alkyl)group; and W is oxygen.
 80. The compound according to claim 14, whereinX₁ is an NH or N(lower alkyl) group; and W is oxygen.